NM_020374.4(FERRY3):c.1360C>T (p.Arg454Ter) AND Intellectual disability, autosomal recessive 66

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000723367.5

Allele description [Variation Report for NM_020374.4(FERRY3):c.1360C>T (p.Arg454Ter)]

NM_020374.4(FERRY3):c.1360C>T (p.Arg454Ter)

Gene:

FERRY3:FERRY endosomal RAB5 effector complex subunit 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.32

Genomic location:

Preferred name:

NM_020374.4(FERRY3):c.1360C>T (p.Arg454Ter)

Other names:

C12ORF4, ARG454TER

HGVS:

NC_000012.12:g.4500218G>A
NG_051648.1:g.43291C>T
NM_001304811.2:c.1360C>T
NM_001346153.2:c.1231C>T
NM_001346155.2:c.1231C>T
NM_001346156.2:c.841C>T
NM_001346157.2:c.712C>T
NM_001352962.2:c.508C>T
NM_020374.4:c.1360C>TMANE SELECT
NP_001291740.1:p.Arg454Ter
NP_001333082.1:p.Arg411Ter
NP_001333084.1:p.Arg411Ter
NP_001333085.1:p.Arg281Ter
NP_001333086.1:p.Arg238Ter
NP_001339891.1:p.Arg170Ter
NP_065107.1:p.Arg454Ter
NC_000012.11:g.4609384G>A
NM_020374.2:c.1360C>T
NM_020374.3:c.1360C>T
NR_144379.2:n.1339C>T
NR_144380.2:n.1012C>T
NR_144382.2:n.809C>T

Protein change:

R170*; ARG454TER

Links:

OMIM: 616082.0003; dbSNP: rs749969789

NCBI 1000 Genomes Browser:

rs749969789

Molecular consequence:

NR_144379.2:n.1339C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_144380.2:n.1012C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_144382.2:n.809C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001304811.2:c.1360C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001346153.2:c.1231C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001346155.2:c.1231C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001346156.2:c.841C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001346157.2:c.712C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001352962.2:c.508C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_020374.4:c.1360C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Intellectual disability, autosomal recessive 66
Synonyms:: Mental retardation, autosomal recessive 66
Identifiers:: MONDO: MONDO:0032605; MedGen: C4748732; OMIM: 618221

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000854767	OMIM	no assertion criteria provided	Pathogenic (Dec 22, 2021)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001245382	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 14, 2020)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 28097321, 25741868
SCV001443032	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2020)	biparental	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002058748	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:28097321

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.

Reuter MS, Tawamie H, Buchert R, Hosny Gebril O, Froukh T, Thiel C, Uebe S, Ekici AB, Krumbiegel M, Zweier C, Hoyer J, Eberlein K, Bauer J, Scheller U, Strom TM, Hoffjan S, Abdelraouf ER, Meguid NA, Abboud A, Al Khateeb MA, Fakher M, Hamdan S, et al.

JAMA Psychiatry. 2017 Mar 1;74(3):293-299. doi: 10.1001/jamapsychiatry.2016.3798.

PubMed [citation]

PMID:: 28097321

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000854767.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 sisters with a nonsyndromic intellectual developmental disorder (MRT66; 618221) from a consanguineous Turkish family, Reuter et al. (2017) identified homozygosity for a c.1360C-T transition (c.1360C-T, NM_020374.2) in the C12ORF4 gene, resulting in a premature termination codon substituting for the arginine at codon 454 (R454X). This variant was not identified in gnomAD.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From SIB Swiss Institute of Bioinformatics, SCV001245382.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as likely pathogenic for Mental retardation, autosomal recessive 66. The following ACMG Tag(s) were applied: PM2, PVS1-Strong.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001443032.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2,PM3_Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002058748.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000592164, PMID:28097321). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000025, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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