rs876658008

Positions:

• chr15-43612379-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_153700.2(STRC):​c.2914C>T​(p.Arg972Trp) variant causes a missense, splice region change. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: STRC NM_153700.2 missense, splice_region
• Scores: Splicing: ADA: 0.6879
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.2914C>T	p.Arg972Trp	missense_variant, splice_region_variant	10/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.2914C>T	p.Arg972Trp	missense_variant, splice_region_variant	10/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 26, 2022

The p.Arg972Trp variant in STRC has been reported in one individual with hearing loss (Miyagawa 2014). This individual was not tested for copy number variants and therefore it is not known if they also had a deletion of STRC (the most common type of pathogenic variant for this gene), and a second variant was not reported. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that the variant may impact the protein; however this information is not sufficient to determine pathogenicity. In summary, the clinical significance of the p.Arg972Trp variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.042	D;T
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.42		Loss of disorder (P = 0.0057);.;
MVP		0.86
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.22
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876658008; hg19: chr15-43904577;