rs876658009

Variant names:

• chr15-43610406-A-C
• rs876658009
• NM_153700.2:c.3404T>G

Variant summary

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

The NM_153700.2(STRC):​c.3404T>G​(p.Leu1135Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 10)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60
• 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

ACMG classification

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

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.3404T>G	p.Leu1135Arg	missense_variant	Exon 15 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.3404T>G	p.Leu1135Arg	missense_variant	Exon 15 of 29	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD2 exomes AF: 0.0000143 AC: 1 AN: 70132 AF XY: 0.0000285

Gnomad AFR exome AF: 0.000175

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000216 AC: 1 AN: 462578 Hom.: 0 Cov.: 6 AF XY: 0.00000411 AC XY: 1 AN XY: 243432

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000752 AC: 1 AN: 13298

American (AMR) AF: 0.00 AC: 0 AN: 27462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13294

East Asian (EAS) AF: 0.00 AC: 0 AN: 25880

South Asian (SAS) AF: 0.00 AC: 0 AN: 51294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1784

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 278616

Other (OTH) AF: 0.00 AC: 0 AN: 24358

⚠️ 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.: 10

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 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.Leu1135Arg 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 analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu1135Arg variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.14	T
PhyloP100		5.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.44		Gain of solvent accessibility (P = 0.0638);
MVP		0.84
ClinPred		0.61	D
GERP RS		3.8
Varity_R		0.38
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs876658009; hg19: chr15-43902604;