19-3585654-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_133261.3(GIPC3):c.57G>T(p.Ala19Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,219,268 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

GIPC3
NM_133261.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.326

Publications

0 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=-0.65).

BP6

Variant 19-3585654-G-T is Benign according to our data. Variant chr19-3585654-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 262317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.326 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000133 (20/150920) while in subpopulation SAS AF = 0.00145 (7/4812). AF 95% confidence interval is 0.000683. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3 link	c.57G>T	p.Ala19Ala	synonymous_variant	Exon 1 of 6	ENST00000644452.3	NP_573568.1	Q8TF64
GIPC3	NM_001411144.1 link	c.57G>T	p.Ala19Ala	synonymous_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.57G>T	p.Ala19Ala	synonymous_variant	Exon 1 of 6		NM_133261.3	ENSP00000493901.2		Q8TF64
GIPC3	ENST00000644946.1 link	c.57G>T	p.Ala19Ala	synonymous_variant	Exon 1 of 6			ENSP00000495068.1		A0A2R8Y651

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

150812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000593

AC:

AN:

3372

AF XY:

0.000988

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

180

AN:

1068348

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

108

AN XY:

510478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21584

American (AMR)

AF:

0.000137

AC:

AN:

7312

Ashkenazi Jewish (ASJ)

AF:

0.000239

AC:

AN:

12560

East Asian (EAS)

AF:

0.0000425

AC:

AN:

23518

South Asian (SAS)

AF:

0.00328

AC:

AN:

20756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23210

Middle Eastern (MID)

AF:

0.00287

AC:

AN:

2790

European-Non Finnish (NFE)

AF:

0.0000885

AC:

AN:

914944

Other (OTH)

AF:

0.000432

AC:

AN:

41674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000133

AC:

AN:

150920

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

73730

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.000132

AC:

AN:

15146

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00145

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67566

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GIPC3: BP4, BP7 -

Mar 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala19Ala in exon 1 of GIPC3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0/0 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s754337950). -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 15

Benign:1

Jul 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.9

(source)

DANN

Benign

0.91

PhyloP100

-0.33

PromoterAI

-0.030

Neutral

(source)

Mutation Taster

=100/0

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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19-3585654-G-T

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