Variant chr12-4518790-ACTTT-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_020374.4(C12orf4):c.815_818del(p.Glu272ValfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000021 in 1,426,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

C12orf4
NM_020374.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.80

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 12-4518790-ACTTT-A is Pathogenic according to our data. Variant chr12-4518790-ACTTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 2197319.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.815_818del	p.Glu272ValfsTer6	frameshift_variant	7/14	ENST00000261250.8	NP_065107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
C12orf4	ENST00000261250.8 linkuse as main transcript	c.815_818del	p.Glu272ValfsTer6	frameshift_variant	7/14	1	NM_020374.4	ENSP00000261250	P1
C12orf4	ENST00000545746.5 linkuse as main transcript	c.815_818del	p.Glu272ValfsTer6	frameshift_variant	7/14	1		ENSP00000439996	P1
C12orf4	ENST00000541014.5 linkuse as main transcript	c.296_299del	p.Glu99ValfsTer6	frameshift_variant	6/8	5		ENSP00000440820
C12orf4	ENST00000544697.1 linkuse as main transcript	c.210-539_210-536del		intron_variant, NMD_transcript_variant		5		ENSP00000439471

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000845

AC:

AN:

236676

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128086

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000622

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1426718

Hom.:

AF XY:

0.00000141

AC XY:

AN XY:

709554

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000473

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:

9.16e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

This sequence change creates a premature translational stop signal (p.Glu272Valfs*6) in the C12orf4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C12orf4 are known to be pathogenic (PMID: 27311568). This variant is present in population databases (rs750549000, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with C12orf4-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: -16

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