Variant 12-4517145-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The ENST00000261250.8(C12orf4):c.1078C>T(p.Arg360Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000346 in 1,589,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

C12orf4
ENST00000261250.8 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.34

Variant links:

Genes affected

C12orf4 (HGNC:1184): (FERRY endosomal RAB5 effector complex subunit 3) This gene is highly conserved from nematodes to humans. In rat, the orthologous gene encodes a cytoplasmic protein that is involved in mast cell degranulation. The human gene has been implicated in autosomal recessive intellectual disability. [provided by RefSeq, Sep 2016]

C12orf4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-4517145-G-A is Pathogenic according to our data. Variant chr12-4517145-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977085.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C12orf4	NM_020374.4 linkuse as main transcript	c.1078C>T	p.Arg360Ter	stop_gained	9/14	ENST00000261250.8	NP_065107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C12orf4	ENST00000261250.8 linkuse as main transcript	c.1078C>T	p.Arg360Ter	stop_gained	9/14	1	NM_020374.4	ENSP00000261250	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000295

AC:

AN:

237516

Hom.:

AF XY:

0.0000466

AC XY:

AN XY:

128726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000636

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000355

AC:

AN:

1437800

Hom.:

Cov.:

AF XY:

0.0000378

AC XY:

AN XY:

714464

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000418

Gnomad4 OTH exome

AF:

0.0000674

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000929

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 66

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

May 28, 2020

This C12orf4 variant (rs374645146) is rare (<0.1%) in a large population dataset (gnomAD: 8/268900 total alleles; 0.003%; no homozygotes) and has not been reported previously in the literature to our knowledge. This nonsense variant results in a premature stop codon in exon 9 likely leading to nonsense?mediated decay and lack of protein production. We consider this variant to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.54

MutationTaster

Benign

1.0

A;A

Vest4

0.32

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: 44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over