19-3589437-C-T

Position:

• chr19-3589437-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133261.3(GIPC3):​c.593-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,608,168 control chromosomes in the GnomAD database, including 18,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (5207 hom., cov: 31)
  • Exomes 𝑓: 0.12 (13676 hom.)
• Consequence: GIPC3 NM_133261.3 splice_region, intron
• Scores: Splicing: ADA: 0.000009590
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.621

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-3589437-C-T is Benign according to our data. Variant chr19-3589437-C-T is described in ClinVar as [Benign]. Clinvar id is 46572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.593-6C>T		splice_region_variant, intron_variant		ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.593-6C>T		splice_region_variant, intron_variant			NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3	c.593-6C>T		splice_region_variant, intron_variant			NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1	c.593-6C>T		splice_region_variant, intron_variant				ENSP00000495068.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31392 AN: 151810 Hom.: 5183 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0488

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0762

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.123 AC: 30853 AN: 251216 Hom.: 3132 AF XY: 0.117 AC XY: 15868 AN XY: 135866

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.0715

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0469

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.0788

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.122 AC: 177041 AN: 1456240 Hom.: 13676 Cov.: 31 AF XY: 0.120 AC XY: 86665 AN XY: 724818

Gnomad4 AFR exome AF: 0.485

Gnomad4 AMR exome AF: 0.0771

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0483

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.0804

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.207 AC: 31464 AN: 151928 Hom.: 5207 Cov.: 31 AF XY: 0.201 AC XY: 14928 AN XY: 74292

Gnomad4 AFR AF: 0.466

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.0487

Gnomad4 SAS AF: 0.0971

Gnomad4 FIN AF: 0.0762

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.166

Alfa AF: 0.107 Hom.: 431

Bravo AF: 0.222

Asia WGS AF: 0.102 AC: 356 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.117

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	Eurofins Ntd Llc (ga)	Mar 21, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	593-6C>T in Intron 03 of GIPC3: This variant is not expected to have clinical si gnificance because it has been identified in 44.6% (1667/3738) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs10426399). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	-0.55
CADD	Benign	0.95
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000096
dbscSNV1_RF	Benign	0.0020
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: rs10426399; hg19: chr19-3589435; COSMIC: COSV59259169;