Variant chr19-3585680-CG-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_133261.3(GIPC3):c.85delG(p.Ala29ProfsTer68) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000617 in 1,361,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: -3.00

Variant links:

Genes affected

GIPC3 (HGNC:18183): (GIPC PDZ domain containing family member 3) The protein encoded by this gene belongs to the GIPC family. Studies in mice suggest that this gene is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion in the ear. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2011]

GIPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-3585680-CG-C is Pathogenic according to our data. Variant chr19-3585680-CG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3067408.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3 link	c.85delG	p.Ala29ProfsTer68	frameshift_variant	Exon 1 of 6	ENST00000644452.3	NP_573568.1	Q8TF64
GIPC3	NM_001411144.1 link	c.85delG	p.Ala29ProfsTer68	frameshift_variant	Exon 1 of 6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3 link	c.85delG	p.Ala29ProfsTer68	frameshift_variant	Exon 1 of 6		NM_133261.3	ENSP00000493901.2		Q8TF64
GIPC3	ENST00000644946.1 link	c.85delG	p.Ala29ProfsTer68	frameshift_variant	Exon 1 of 6			ENSP00000495068.1		A0A2R8Y651

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000739

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000272

AC:

AN:

73508

Hom.:

AF XY:

0.0000233

AC XY:

AN XY:

42830

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:

0.0000745

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000644

AC:

AN:

1210628

Hom.:

Cov.:

AF XY:

0.0000657

AC XY:

AN XY:

593260

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000775

Gnomad4 OTH exome

AF:

0.0000418

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151050

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

73722

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000739

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000947

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GIPC3: PM2, PVS1:Moderate -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 04, 2017

The p.Ala29ProfsX68 variant in GIPC3 has not been previously reported in individuals with hearing loss and was present in 0.06% (1/1748) of European chromosomes studies by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs756840753). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 29 and leads to a premature termination codon 68 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala29ProfsX68 variant is likely pathogenic for autosomal recessive hearing loss based upon predicted impact and low allele frequency. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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