rs142652588
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_153676.4(USH1C):c.2419G>A(p.Gly807Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000153 in 1,614,152 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
USH1C
NM_153676.4 missense
NM_153676.4 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 4.78
Genes affected
USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.745
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1C | NM_153676.4 | c.2419G>A | p.Gly807Ser | missense_variant | 24/27 | ENST00000005226.12 | |
USH1C | NM_005709.4 | c.1519G>A | p.Gly507Ser | missense_variant | 19/21 | ENST00000318024.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.2419G>A | p.Gly807Ser | missense_variant | 24/27 | 5 | NM_153676.4 | ||
USH1C | ENST00000318024.9 | c.1519G>A | p.Gly507Ser | missense_variant | 19/21 | 1 | NM_005709.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152162Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000171 AC: 43AN: 251464Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135896
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GnomAD4 exome AF: 0.000155 AC: 226AN: 1461872Hom.: 0 Cov.: 35 AF XY: 0.000153 AC XY: 111AN XY: 727234
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74460
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 507 of the USH1C protein (p.Gly507Ser). This variant is present in population databases (rs142652588, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 178562). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Usher syndrome type 1C Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 15, 2013 | The Gly807Ser variant in USH1C has not been previously reported in individuals w ith hearing loss, but has been identified in 0.03% (3/8586) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs142652588). Computational analyses (biochemical amino acid proper ties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong suppor t for or against an impact to the protein. In summary, additional data is neede d to determine the clinical significance of this variant. - |
Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;P;.
Vest4
MVP
MPC
0.39
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