rs8113232

Positions:

• chr19-3586545-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_133261.3(GIPC3):​c.276G>A​(p.Leu92=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.913

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.276G>A	p.Leu92=	synonymous_variant	2/6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.276G>A	p.Leu92=	synonymous_variant	2/6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3	c.276G>A	p.Leu92=	synonymous_variant	2/6		NM_133261.3	ENSP00000493901	P1
GIPC3	ENST00000644946.1	c.276G>A	p.Leu92=	synonymous_variant	2/6			ENSP00000495068

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34745 AN: 151990 Hom.: 6432 Cov.: 31

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

GnomAD3 exomes AF: 0.137 AC: 34256 AN: 250884 Hom.: 3916 AF XY: 0.130 AC XY: 17681 AN XY: 135786

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 SAS exome AF: 0.126

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.: 39 AF XY: 0.132 AC XY: 95623 AN XY: 727008

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.0878

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.0495

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0897

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.229 AC: 34820 AN: 152108 Hom.: 6459 Cov.: 31 AF XY: 0.222 AC XY: 16520 AN XY: 74366

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0511

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0837

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.185

Alfa AF: 0.143 Hom.: 3723

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

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.0
DANN	Benign	0.66

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

Other links and lift over

dbSNP: rs8113232; hg19: chr19-3586543;