chr19-3585682-GC-G

Position:

• chr19-3585682-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_133261.3(GIPC3):​c.87del​(p.Ala30ArgfsTer67) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GIPC3 NM_133261.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.70

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-3585682-GC-G is Pathogenic according to our data. Variant chr19-3585682-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3367081.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3	c.87del	p.Ala30ArgfsTer67	frameshift_variant	1/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.87del	p.Ala30ArgfsTer67	frameshift_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.87del	p.Ala30ArgfsTer67	frameshift_variant	1/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.87del	p.Ala30ArgfsTer67	frameshift_variant	1/6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 15 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The frameshift variant c.87del (p.Ala30ArgfsTer67) in the GIPC3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is absent in the gnomAD Exomes. This variant causes a frameshift starting with codon Alanine 30, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 67 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing (Charizopoulou et al., 2011). For these reasons, this variant has been classified as Likely Pathogenic -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-3585680;