rs876658008

Variant names:

• chr15-43612379-G-A
• rs876658008
• NM_153700.2:c.2914C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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

ENSG00000309475 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.2914C>T	p.Arg972Trp	missense_variant, splice_region_variant	Exon 10 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.2914C>T	p.Arg972Trp	missense_variant, splice_region_variant	Exon 10 of 29	5	NM_153700.2	ENSP00000401513.2

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

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		3.7
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
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs876658008; hg19: chr15-43904577;