19-3585680-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_133261.3(GIPC3):c.85del(p.Ala29ProfsTer68) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000617 in 1,361,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: GIPC3 NM_133261.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -3.00

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 11 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 19-3585680-CG-C is Pathogenic according to our data. Variant chr19-3585680-CG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3067408.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3	c.85del	p.Ala29ProfsTer68	frameshift_variant	1/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.85del	p.Ala29ProfsTer68	frameshift_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.85del	p.Ala29ProfsTer68	frameshift_variant	1/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.85del	p.Ala29ProfsTer68	frameshift_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.0000397 AC: 6 AN: 151050 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000739

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000272 AC: 2 AN: 73508 Hom.: 0 AF XY: 0.0000233 AC XY: 1 AN XY: 42830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000745

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000644 AC: 78 AN: 1210628 Hom.: 0 Cov.: 31 AF XY: 0.0000657 AC XY: 39 AN XY: 593260

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000775

Gnomad4 OTH exome AF: 0.0000418

GnomAD4 genome AF: 0.0000397 AC: 6 AN: 151050 Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4 AN XY: 73722

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000739

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000947 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 04, 2017

The p.Ala29ProfsX68 variant in GIPC3 has not been previously reported in individuals with hearing loss and was present in 0.06% (1/1748) of European chromosomes studies by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs756840753). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 29 and leads to a premature termination codon 68 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala29ProfsX68 variant is likely pathogenic for autosomal recessive hearing loss based upon predicted impact and low allele frequency. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

GIPC3: PM2, PVS1:Moderate -

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

LitVar

Other links and lift over

dbSNP: rs756840753; hg19: chr19-3585678;