chr19-3585680-CG-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_133261.3(GIPC3):c.85delG(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
Consequence
NM_133261.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GIPC3 | ENST00000644452.3 | c.85delG | p.Ala29ProfsTer68 | frameshift_variant | Exon 1 of 6 | NM_133261.3 | ENSP00000493901.2 | |||
GIPC3 | ENST00000644946.1 | c.85delG | p.Ala29ProfsTer68 | frameshift_variant | Exon 1 of 6 | ENSP00000495068.1 |
Frequencies
GnomAD3 genomes AF: 0.0000397 AC: 6AN: 151050Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000272 AC: 2AN: 73508Hom.: 0 AF XY: 0.0000233 AC XY: 1AN XY: 42830
GnomAD4 exome AF: 0.0000644 AC: 78AN: 1210628Hom.: 0 Cov.: 31 AF XY: 0.0000657 AC XY: 39AN XY: 593260
GnomAD4 genome AF: 0.0000397 AC: 6AN: 151050Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4AN XY: 73722
ClinVar
Submissions by phenotype
not provided Uncertain:2
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -
GIPC3: PM2, PVS1:Moderate -
Rare genetic deafness Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at