rs876657725
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_153700.2(STRC):c.3217C>T(p.Arg1073*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000025 ( 0 hom., cov: 15)
Exomes 𝑓: 0.0000070 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
STRC
NM_153700.2 stop_gained
NM_153700.2 stop_gained
Scores
1
1
5
Clinical Significance
Conservation
PhyloP100: -0.392
Genes affected
STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 15-43611237-G-A is Pathogenic according to our data. Variant chr15-43611237-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 228402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43611237-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000246 AC: 3AN: 122150Hom.: 0 Cov.: 15
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GnomAD3 exomes AF: 0.0000104 AC: 1AN: 95826Hom.: 0 AF XY: 0.0000200 AC XY: 1AN XY: 49878
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000698 AC: 5AN: 716188Hom.: 0 Cov.: 10 AF XY: 0.00000540 AC XY: 2AN XY: 370656
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GnomAD4 genome AF: 0.0000245 AC: 3AN: 122264Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0AN XY: 58034
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 16 Pathogenic:2
Pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Feb 28, 2023 | This variant occurred in compound heterozygosity with an STRC full gene deletion in two siblings with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). The family has no other history of hearing loss. This variant is a nonsense leading to an early stop at position 1073 of 1775 in the stereocilin protein. As of January 2023, this variant has been reported to ClinVar as pathogenic and is found in 1 heterozygote on gnomAD. Based on the prediction that this variant leads to a truncated protein, compound heterozygosity with a loss-of-function variant, co-segregation within the family, and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
STRC-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 04, 2023 | The STRC c.3217C>T variant is predicted to result in premature protein termination (p.Arg1073*). This variant has been reported as pathogenic in patients with nonsyndromic hearing loss (Marková et al. 2018. PubMed ID: 29425068; Table S1, Safka Brozkova et al. 2020. PubMed ID: 32860223). This variant is reported in 0.0030% of alleles in individuals of European (Non-Finnish) descent in gnomAD, although due to sequence paralogy the allele frequency estimates at this locus may be unreliable. Nonsense variants in STRC are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2016 | The p.Arg1073X variant in STRC has been previously reported by our laboratory in 1 individual with hearing loss, who was compound heterozygous for a second path ogenic variant in STRC. Data from large population studies is insufficient to as sess the frequency of this variant. This nonsense variant leads to a premature t ermination codon at position 1073, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as path ogenic for hearing loss in an autosomal recessive manner based on its predicted impact to the protein. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at