rs727503062

Positions:

chr19-3585719-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_133261.3(GIPC3):c.122C>A(p.Thr41Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000741 in 1,483,562 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 (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.38

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

PP5

Variant 19-3585719-C-A is Pathogenic according to our data. Variant chr19-3585719-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-3585719-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3 linkuse as main transcript	c.122C>A	p.Thr41Lys	missense_variant	1/6	ENST00000644452.3
GIPC3	NM_001411144.1 linkuse as main transcript	c.122C>A	p.Thr41Lys	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3 linkuse as main transcript	c.122C>A	p.Thr41Lys	missense_variant	1/6		NM_133261.3	P1
GIPC3	ENST00000644946.1 linkuse as main transcript	c.122C>A	p.Thr41Lys	missense_variant	1/6

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000196

AC:

AN:

102036

Hom.:

AF XY:

0.00

AC XY:

AN XY:

56872

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:

0.0000278

Gnomad OTH exome

AF:

0.000351

GnomAD4 exome

AF:

0.00000676

AC:

AN:

1331656

Hom.:

Cov.:

AF XY:

0.00000761

AC XY:

AN XY:

656664

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:

0.0000275

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000479

Gnomad4 OTH exome

AF:

0.0000367

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74180

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000870

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GIPC3 protein function. ClinVar contains an entry for this variant (Variation ID: 163502). This missense change has been observed in individuals with nonsyndromic deafness (PMID: 23510777, 32747562, 32864763). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 41 of the GIPC3 protein (p.Thr41Lys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32864763, 23510777, 32747562) -

Autosomal recessive nonsyndromic hearing loss 15

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jun 17, 2023

Now, we have found stronger evidence of pathogenicity and changed this variant classification from uncertain significance to likely pathogenic (PM2,PM3_Moderate ,PP3_Moderate; according to ACMG Guidelines, 2015) -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2016

The p.Thr41Lys variant in GIPC3 has been previously identified in one consanguin eous Saudi Arabian family with prelingual severe to profound sensorineural heari ng loss and was not identified among 400 ethnically matched control chromosomes (Ramzan 2013). The Thr41Lys variant segregated in the homozygous state in five a ffected siblings, while the parents and two unaffected siblings were either hete rozygous for the variant or were wild-type (Ramzan 2013). However, the reported segregation data cannot rule out linkage disequilibrium between the Thr41Lys var iant and another causative variant. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pa thogenic based on the segregation data from the previously reported family. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

D;D;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

-0.048

MutationAssessor

Uncertain

2.6

M;M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-3.5

D;.;.

REVEL

Pathogenic

0.77

Sift

Benign

0.059

T;.;.

Sift4G

Benign

0.086

T;.;.

Polyphen

0.65

P;P;.

Vest4

0.89

MVP

0.87

MPC

0.21

ClinPred

0.94

GERP RS

3.6

Varity_R

0.45

gMVP

0.79

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