Variant 19-3585647-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_133261.3(GIPC3):c.50C>G(p.Ala17Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,206,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.109

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074192435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIPC3	NM_133261.3 linkuse as main transcript	c.50C>G	p.Ala17Gly	missense_variant	1/6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1 linkuse as main transcript	c.50C>G	p.Ala17Gly	missense_variant	1/6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3 linkuse as main transcript	c.50C>G	p.Ala17Gly	missense_variant	1/6		NM_133261.3	ENSP00000493901	P1
GIPC3	ENST00000644946.1 linkuse as main transcript	c.50C>G	p.Ala17Gly	missense_variant	1/6			ENSP00000495068

Frequencies

GnomAD3 genomes

AF:

0.0000596

AC:

AN:

150982

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1055672

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

503490

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:

0.0000452

Gnomad4 OTH exome

AF:

0.0000244

GnomAD4 genome

AF:

0.0000596

AC:

AN:

150982

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73696

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:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 228698). This variant has not been reported in the literature in individuals affected with GIPC3-related conditions. 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 alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 17 of the GIPC3 protein (p.Ala17Gly). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ala17Gly vari ant in GIPC3 has not been previously reported in individuals with hearing loss a nd was absent from large population studies. Computational prediction tools and conservation analyses suggest that the p.Ala17Gly variant may not impact the pro tein, though this information is not predictive enough to rule out pathogenicity . In summary, while the clinical significance of the p.Ala17Gly variant is unce rtain, conservation and computational data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.5

DANN

Benign

0.97

DEOGEN2

Benign

0.071

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.31

.;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.074

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.55

N;N;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.17

N;.;.

REVEL

Benign

0.19

Sift

Benign

0.41

T;.;.

Sift4G

Benign

0.42

T;.;.

Polyphen

0.0

B;B;.

Vest4

0.052

MutPred

0.070

Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);

MVP

0.61

MPC

0.10

ClinPred

0.11

GERP RS

2.5

Varity_R

0.054

gMVP

0.26

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