chr19-3590072-C-T

Position:

chr19-3590072-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_133261.3(GIPC3):c.821C>T(p.Ala274Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,611,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.34

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 Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020741433).

BP6

Variant 19-3590072-C-T is Benign according to our data. Variant chr19-3590072-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517347.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000404 (59/1459120) while in subpopulation MID AF= 0.00486 (28/5758). AF 95% confidence interval is 0.00346. There are 0 homozygotes in gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIPC3	NM_133261.3 linkuse as main transcript	c.821C>T	p.Ala274Val	missense_variant	6/6	ENST00000644452.3	NP_573568.1	Q8TF64
GIPC3	NM_001411144.1 linkuse as main transcript	c.834C>T	p.Ser278Ser	synonymous_variant	6/6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3 linkuse as main transcript	c.821C>T	p.Ala274Val	missense_variant	6/6		NM_133261.3	ENSP00000493901.2		Q8TF64
GIPC3	ENST00000644946.1 linkuse as main transcript	c.834C>T	p.Ser278Ser	synonymous_variant	6/6			ENSP00000495068.1		A0A2R8Y651

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000371

AC:

AN:

242666

Hom.:

AF XY:

0.0000531

AC XY:

AN XY:

131898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000595

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000664

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1459120

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

725720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000254

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 274 of the GIPC3 protein (p.Ala274Val). This variant is present in population databases (rs149028750, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with GIPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 517347). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 03, 2017

p.Ala274Val in exon 6 of GIPC3: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >10 mammals have a valine (Val) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identified in 4/54114 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs149028750). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.0050

DANN

Benign

0.94

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.23

.;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.79

N;.

REVEL

Benign

0.13

Sift

Benign

0.33

T;.

Sift4G

Benign

0.28

T;.

Polyphen

0.0010

B;B

Vest4

0.045

MVP

0.46

MPC

0.099

ClinPred

0.039

GERP RS

-8.6

Varity_R

0.029

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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