chr15-43616689-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_153700.2(STRC):​c.877G>A​(p.Gly293Ser) variant causes a missense, splice region change. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 13)
Exomes 𝑓: 0.0000076 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

STRC
NM_153700.2 missense, splice_region

Scores

4
9
5
Splicing: ADA: 0.9734
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.30

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • nonsyndromic genetic hearing loss
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • autosomal recessive nonsyndromic hearing loss 16
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STRCNM_153700.2 linkc.877G>A p.Gly293Ser missense_variant, splice_region_variant Exon 4 of 29 ENST00000450892.7 NP_714544.1 Q7RTU9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STRCENST00000450892.7 linkc.877G>A p.Gly293Ser missense_variant, splice_region_variant Exon 4 of 29 5 NM_153700.2 ENSP00000401513.2 Q7RTU9
ENSG00000284772ENST00000643290.1 linkn.*1040G>A splice_region_variant, non_coding_transcript_exon_variant Exon 6 of 9 ENSP00000495476.1 A0A2R8Y6Q2
ENSG00000284772ENST00000643290.1 linkn.*1040G>A 3_prime_UTR_variant Exon 6 of 9 ENSP00000495476.1 A0A2R8Y6Q2

Frequencies

GnomAD3 genomes
Cov.:
13
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000759
AC:
3
AN:
395208
Hom.:
0
Cov.:
0
AF XY:
0.00000960
AC XY:
2
AN XY:
208340
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
10552
American (AMR)
AF:
0.00
AC:
0
AN:
17000
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
12104
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26958
South Asian (SAS)
AF:
0.0000224
AC:
1
AN:
44554
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
24550
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1714
European-Non Finnish (NFE)
AF:
0.00000851
AC:
2
AN:
235072
Other (OTH)
AF:
0.00
AC:
0
AN:
22704
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.258
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
13

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 11, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Gly293Ser variant in STRC has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation a nalyses do not provide strong support for or against an impact to the protein. I n summary, the clinical significance of the p.Gly293Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.81
T;T
M_CAP
Benign
0.042
D
MetaRNN
Uncertain
0.58
D;D
MetaSVM
Uncertain
0.13
D
PhyloP100
5.3
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.91
N;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0060
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;.
Vest4
0.79
MutPred
0.36
Loss of catalytic residue at V294 (P = 0.1017);.;
MVP
0.83
ClinPred
0.92
D
GERP RS
5.0
Varity_R
0.16
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Pathogenic
0.83
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

Other links and lift over

dbSNP: rs876658010; hg19: chr15-43908887; API