chr19-3585601-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_133261.3(GIPC3):c.4G>A(p.Glu2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,155,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

GIPC3
NM_133261.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.07

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 15
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GIPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03703049).

BP6

Variant 19-3585601-G-A is Benign according to our data. Variant chr19-3585601-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505606.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00105 (160/151826) while in subpopulation NFE AF = 0.00125 (85/67888). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3 link	c.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 6	ENST00000644452.3	NP_573568.1	Q8TF64
GIPC3	NM_001411144.1 link	c.4G>A	p.Glu2Lys	missense_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.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 6		NM_133261.3	ENSP00000493901.2		Q8TF64
GIPC3	ENST00000644946.1 link	c.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 6			ENSP00000495068.1		A0A2R8Y651

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

151720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00538

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00432

AC:

AN:

694

AF XY:

0.00476

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00455

Gnomad NFE exome

AF:

0.00437

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00108

AC:

1087

AN:

1003964

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

503

AN XY:

474734

show subpopulations

African (AFR)

AF:

0.0000499

AC:

AN:

20030

American (AMR)

AF:

0.000512

AC:

AN:

5862

Ashkenazi Jewish (ASJ)

AF:

0.00215

AC:

AN:

10692

East Asian (EAS)

AF:

0.00

AC:

AN:

18518

South Asian (SAS)

AF:

0.00

AC:

AN:

18894

European-Finnish (FIN)

AF:

0.00457

AC:

AN:

16864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2452

European-Non Finnish (NFE)

AF:

0.00106

AC:

926

AN:

872774

Other (OTH)

AF:

0.00150

AC:

AN:

37878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

151826

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41510

American (AMR)

AF:

0.000131

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00538

AC:

AN:

10418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

67888

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.000623

ExAC

AF:

0.000158

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Jul 25, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 07, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu2Lys variant in GIPC3 has not been previously reported in individuals w ith hearing loss or in large population studies. Computational prediction tools and conservation analysis suggest that the p.Glu2Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. In summary, the clinical significance of the p.Glu2Lys variant is uncertain . -

GIPC3-related disorder

Benign:1

Apr 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.47

.;T;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.1

L;L;.

PhyloP100

2.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.84

N;.;.

REVEL

Benign

0.25

Sift

Pathogenic

0.0

D;.;.

Sift4G

Benign

0.064

T;.;.

Polyphen

0.0

B;B;.

Vest4

0.19

MVP

0.72

MPC

0.11

ClinPred

0.27

GERP RS

2.5

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.26

gMVP

0.51

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over