19-3586545-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_133261.3(GIPC3):c.276G>A(p.Leu92Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,494 control chromosomes in the GnomAD database, including 23,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 6459 hom., cov: 31)

Exomes 𝑓: 0.13 ( 16638 hom. )

Consequence

GIPC3
NM_133261.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.913

Publications

24 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 19-3586545-G-A is Benign according to our data. Variant chr19-3586545-G-A is described in ClinVar as [Benign]. Clinvar id is 46571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.913 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3 link	c.276G>A	p.Leu92Leu	synonymous_variant	Exon 2 of 6	ENST00000644452.3	NP_573568.1	Q8TF64
GIPC3	NM_001411144.1 link	c.276G>A	p.Leu92Leu	synonymous_variant	Exon 2 of 6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3 link	c.276G>A	p.Leu92Leu	synonymous_variant	Exon 2 of 6		NM_133261.3	ENSP00000493901.2		Q8TF64
GIPC3	ENST00000644946.1 link	c.276G>A	p.Leu92Leu	synonymous_variant	Exon 2 of 6			ENSP00000495068.1		A0A2R8Y651

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34745

AN:

151990

Hom.:

6432

Cov.:

show subpopulations

Gnomad AFR

AF:

0.517

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.0512

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.0837

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.128

Gnomad OTH

AF:

0.187

GnomAD2 exomes

AF:

0.137

AC:

34256

AN:

250884

AF XY:

0.130

show subpopulations

Gnomad AFR exome

AF:

0.532

Gnomad AMR exome

AF:

0.0816

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.0486

Gnomad FIN exome

AF:

0.0874

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.133

AC:

194965

AN:

1461386

Hom.:

16638

Cov.:

AF XY:

0.132

AC XY:

95623

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.541

AC:

18112

AN:

33472

American (AMR)

AF:

0.0878

AC:

3925

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

2951

AN:

26132

East Asian (EAS)

AF:

0.0495

AC:

1965

AN:

39700

South Asian (SAS)

AF:

0.125

AC:

10822

AN:

86248

European-Finnish (FIN)

AF:

0.0897

AC:

4773

AN:

53182

Middle Eastern (MID)

AF:

0.147

AC:

849

AN:

5768

European-Non Finnish (NFE)

AF:

0.128

AC:

142394

AN:

1111786

Other (OTH)

AF:

0.152

AC:

9174

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

9385

18770

28155

37540

46925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5338

10676

16014

21352

26690

<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:

0.229

AC:

34820

AN:

152108

Hom.:

6459

Cov.:

AF XY:

0.222

AC XY:

16520

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.517

AC:

21424

AN:

41426

American (AMR)

AF:

0.132

AC:

2017

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

423

AN:

3472

East Asian (EAS)

AF:

0.0511

AC:

264

AN:

5166

South Asian (SAS)

AF:

0.121

AC:

584

AN:

4832

European-Finnish (FIN)

AF:

0.0837

AC:

889

AN:

10624

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.128

AC:

8711

AN:

67988

Other (OTH)

AF:

0.185

AC:

391

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1141

2282

3424

4565

5706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.151

Hom.:

5684

Bravo

AF:

0.244

Asia WGS

AF:

0.126

AC:

439

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.126

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 26, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu92Leu in Exon 02 of GIPC3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 48.7% (1820/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs8113232). -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.0

(source)

DANN

Benign

0.66

PhyloP100

0.91

Mutation Taster

=100/0

polymorphism (auto)

(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