rs876657725

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

Scores

1
1
5

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.392
Variant links:
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]

Genome browser will be placed here

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

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STRCNM_153700.2 linkc.3217C>T p.Arg1073* stop_gained 13/29 ENST00000450892.7 NP_714544.1 Q7RTU9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STRCENST00000450892.7 linkc.3217C>T p.Arg1073* stop_gained 13/295 NM_153700.2 ENSP00000401513.2 Q7RTU9

Frequencies

GnomAD3 genomes
AF:
0.0000246
AC:
3
AN:
122150
Hom.:
0
Cov.:
15
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000542
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000104
AC:
1
AN:
95826
Hom.:
0
AF XY:
0.0000200
AC XY:
1
AN XY:
49878
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000296
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000698
AC:
5
AN:
716188
Hom.:
0
Cov.:
10
AF XY:
0.00000540
AC XY:
2
AN XY:
370656
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000488
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000418
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000245
AC:
3
AN:
122264
Hom.:
0
Cov.:
15
AF XY:
0.00
AC XY:
0
AN XY:
58034
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000542
Gnomad4 OTH
AF:
0.00

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 submitterresearchKing Laboratory, University of WashingtonFeb 28, 2023This 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 providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -
STRC-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 04, 2023The 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 03, 2016The 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
35
DANN
Benign
0.85
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.018
N
Vest4
0.72
GERP RS
-8.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.94
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.94
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876657725; hg19: chr15-43903435; API