chr15-43616689-C-T

Variant names:

• chr15-43616689-C-T
• rs876658010
• NM_153700.2:c.877G>A

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: Splicing: ADA: 0.9734
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30
• Publications: 0 publications found

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

ENSG00000284772 (HGNC:):

ACMG classification

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
STRC	NM_153700.2	c.877G>A	p.Gly293Ser	missense_variant, splice_region_variant	Exon 4 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.877G>A	p.Gly293Ser	missense_variant, splice_region_variant	Exon 4 of 29	5	NM_153700.2	ENSP00000401513.2
ENSG00000284772	ENST00000643290.1	n.*1040G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000495476.1
ENSG00000284772	ENST00000643290.1	n.*1040G>A		3_prime_UTR_variant	Exon 6 of 9			ENSP00000495476.1

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

⚠️ 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.

GnomAD4 genome Cov.: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Other links and lift over

dbSNP: rs876658010; hg19: chr15-43908887;