rs998073430

Positions:

chr19-3585617-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1

The NM_133261.3(GIPC3):c.20G>A(p.Arg7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,164,310 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.661

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_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21502843).

BP6

Variant 19-3585617-G-A is Benign according to our data. Variant chr19-3585617-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517411.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000277 (42/151470) while in subpopulation AFR AF= 0.000869 (36/41442). AF 95% confidence interval is 0.000645. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 31. 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.20G>A	p.Arg7Gln	missense_variant	1/6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1 linkuse as main transcript	c.20G>A	p.Arg7Gln	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.20G>A	p.Arg7Gln	missense_variant	1/6		NM_133261.3	ENSP00000493901	P1
GIPC3	ENST00000644946.1 linkuse as main transcript	c.20G>A	p.Arg7Gln	missense_variant	1/6			ENSP00000495068

Frequencies

GnomAD3 genomes

AF:

0.000277

AC:

AN:

151362

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000871

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000355

AC:

AN:

1012840

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

479546

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000210

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000341

Gnomad4 OTH exome

AF:

0.0000781

GnomAD4 genome

AF:

0.000277

AC:

AN:

151470

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

AN XY:

74040

show subpopulations

Gnomad4 AFR

AF:

0.000869

Gnomad4 AMR

AF:

0.000394

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000404

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 07, 2023	This variant is present in population databases (no rsID available, gnomAD 0.07%). 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 output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 517411). This variant has not been reported in the literature in individuals affected with GIPC3-related conditions. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 7 of the GIPC3 protein (p.Arg7Gln). -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.20G>A (p.R7Q) alteration is located in exon 1 (coding exon 1) of the GIPC3 gene. This alteration results from a G to A substitution at nucleotide position 20, causing the arginine (R) at amino acid position 7 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2017

p.Arg7Gln of GIPC3: This variant is not expected to have clinical significance d ue to a lack of conservation across species, including mammals. Of note, 19 spec ies carry a glutamine (Gln) at this position, supporting that this change may be tolerated. In addition, computational prediction tools do not suggest a high li kelihood of impact to the protein. It has also been identified in 6/8510 African chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/; dbSNP rs998073430). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.080

T;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.45

.;T;T

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.20

N;N;.

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.71

N;.;.

REVEL

Benign

0.18

Sift

Benign

0.093

T;.;.

Sift4G

Benign

0.53

T;.;.

Polyphen

0.0050

B;B;.

Vest4

0.074

MutPred

0.17

Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);

MVP

0.81

MPC

0.12

ClinPred

0.11

GERP RS

0.12

Varity_R

0.042

gMVP

0.31

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