Variant rs727503447 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_153700.2(STRC):c.3275G>A(p.Cys1092Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000064 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000062 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

STRC
NM_153700.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 1.68

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]

STRC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07783142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.3275G>A	p.Cys1092Tyr	missense_variant	13/29	ENST00000450892.7	NP_714544.1	Q7RTU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 link	c.3275G>A	p.Cys1092Tyr	missense_variant	13/29	5	NM_153700.2	ENSP00000401513.2		Q7RTU9

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

125326

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000842

Gnomad ASJ

AF:

0.00242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000236

AC:

AN:

131144

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

70530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000498

Gnomad ASJ exome

AF:

0.00196

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000598

Gnomad OTH exome

AF:

0.000767

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000622

AC:

AN:

1206000

Hom.:

Cov.:

AF XY:

0.0000546

AC XY:

AN XY:

604334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000355

Gnomad4 ASJ exome

AF:

0.00181

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000122

Gnomad4 OTH exome

AF:

0.000173

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000638

AC:

AN:

125326

Hom.:

Cov.:

AF XY:

0.0000837

AC XY:

AN XY:

59752

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000842

Gnomad4 ASJ

AF:

0.00242

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000432

Hom.:

ExAC

AF:

0.0000753

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 28, 2022	PP1, PM2_supporting, PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2024	Identified in the heterozygous state in a patient with hearing loss who also harbored an STRC gene deletion. Parental studies were not conducted to determine if these variant were inherited in the compound heterozygous state (PMID: 29425068); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29425068) -

Autosomal recessive nonsyndromic hearing loss 16

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Jan 07, 2021	The c.3275G>A variant in the STRC gene is a missense variant which results in the substitution of a cysteine residue at amino acid position 1092 for a tyrosine (NP_116023.2). This variant localizes to coding exon 13 of the STRC gene (29 coding exons in total; NM_153700.2). In silico predictors for this variant are not consistent: it is predicted to be neutral to protein structure and/or function by PROVEAN, but is predicted to be damaging by SIFT. This variant is present in the Genome Aggregation Database (gnomAD) at a very low frequency, 0.0209% (32 out of 153,222 alleles), indicating it is not a common benign variant in the populations represented in this database. This variant was reported in a patient with nonsyndromic early-onset hearing loss who was compound heterozygous for this variant and a deletion of the STRC gene (PMID: 29425068). This variant is reported in ClinVar with as a variant of uncertain clinical significance (allele ID# 165318, last accessed 8/11/2020). Given the limited evidence available, the c.3275G>A (p.Cys1092Tyr) variant in STRC is classified as a variant of uncertain clinical significance. Parental studies were not conducted at our laboratory, but this variant was reported to be maternally-inherited in an older sibling. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 25, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys1092Ty r variant in STRC has been previously reported in 1 Caucasian individual with he aring loss (LMM unpublished data). This individual also carried a pathogenic var iant and the p.Arg1073Gln variant of uncertain significance in STRC; however, th e cis/trans configuration of the variants was not determined. Data from large po pulation studies is insufficient to assess the frequency of this variant. Comput ational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspic ion for a pathogenic role based on the previously reported case, the clinical si gnificance of the p.Cys1092Tyr variant is uncertain. -

STRC-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2022

The STRC c.3275G>A variant is predicted to result in the amino acid substitution p.Cys1092Tyr. This variant was reported in a patient with non-syndromic hearing loss in conjunction with a second pathogenic variant (Marková et al. 2018. PubMed ID: 29425068). This variant is reported in 0.21% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-43903377-C-T), although allele frequency data at this locus may be unreliable due to sequence paralogy. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.78

M_CAP

Benign

0.034

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.81

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.36

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0060

Polyphen

0.36

Vest4

0.52

MutPred

0.28

Loss of stability (P = 0.0719);

MVP

0.56

ClinPred

0.054

GERP RS

2.1

Varity_R

0.20

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over