rs121908370
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153676.4(USH1C):c.91C>T(p.Arg31Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,572 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
USH1C
NM_153676.4 stop_gained
NM_153676.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.17
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 Pathogenic. Variant got 18 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 72 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-17533268-G-A is Pathogenic according to our data. Variant chr11-17533268-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17533268-G-A is described in Lovd as [Pathogenic]. Variant chr11-17533268-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1C | NM_153676.4 | c.91C>T | p.Arg31Ter | stop_gained | 2/27 | ENST00000005226.12 | |
USH1C | NM_005709.4 | c.91C>T | p.Arg31Ter | stop_gained | 2/21 | ENST00000318024.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.91C>T | p.Arg31Ter | stop_gained | 2/27 | 5 | NM_153676.4 | ||
USH1C | ENST00000318024.9 | c.91C>T | p.Arg31Ter | stop_gained | 2/21 | 1 | NM_005709.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152042Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251248Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135810
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461530Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727098
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152042Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74254
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 23, 2018 | - - |
Pathogenic, flagged submission | clinical testing | Baylor Genetics | Sep 07, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change creates a premature translational stop signal (p.Arg31*) in the USH1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH1C are known to be pathogenic (PMID: 10973247, 17407589, 20301442, 21203349). This variant is present in population databases (rs121908370, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 11139240, 27440999, 27957503). ClinVar contains an entry for this variant (Variation ID: 5146). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 18, 2016 | - - |
Usher syndrome type 1C Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 25, 2021 | - - |
Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
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