rs727503062
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_133261.3(GIPC3):c.122C>A(p.Thr41Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000741 in 1,483,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
GIPC3
NM_133261.3 missense
NM_133261.3 missense
Scores
7
8
3
Clinical Significance
Conservation
PhyloP100: 5.38
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.891
PP5
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Variant 19-3585719-C-A is Pathogenic according to our data. Variant chr19-3585719-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163502.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}. Variant chr19-3585719-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GIPC3 | NM_133261.3 | c.122C>A | p.Thr41Lys | missense_variant | 1/6 | ENST00000644452.3 | |
GIPC3 | NM_001411144.1 | c.122C>A | p.Thr41Lys | missense_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GIPC3 | ENST00000644452.3 | c.122C>A | p.Thr41Lys | missense_variant | 1/6 | NM_133261.3 | P1 | ||
GIPC3 | ENST00000644946.1 | c.122C>A | p.Thr41Lys | missense_variant | 1/6 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151906Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000196 AC: 2AN: 102036Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 56872
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GnomAD4 exome AF: 0.00000676 AC: 9AN: 1331656Hom.: 0 Cov.: 31 AF XY: 0.00000761 AC XY: 5AN XY: 656664
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151906Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74180
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 21, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GIPC3 protein function. ClinVar contains an entry for this variant (Variation ID: 163502). This missense change has been observed in individuals with nonsyndromic deafness (PMID: 23510777, 32747562, 32864763). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 41 of the GIPC3 protein (p.Thr41Lys). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32864763, 23510777, 32747562) - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 18, 2016 | The p.Thr41Lys variant in GIPC3 has been previously identified in one consanguin eous Saudi Arabian family with prelingual severe to profound sensorineural heari ng loss and was not identified among 400 ethnically matched control chromosomes (Ramzan 2013). The Thr41Lys variant segregated in the homozygous state in five a ffected siblings, while the parents and two unaffected siblings were either hete rozygous for the variant or were wild-type (Ramzan 2013). However, the reported segregation data cannot rule out linkage disequilibrium between the Thr41Lys var iant and another causative variant. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pa thogenic based on the segregation data from the previously reported family. - |
Sensorineural hearing loss disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Aug 04, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.
REVEL
Pathogenic
Sift
Benign
T;.;.
Sift4G
Benign
T;.;.
Polyphen
P;P;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at