chr15-43601535-C-T

Position:

• chr15-43601535-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153700.2(STRC):​c.4562G>A​(p.Arg1521Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,613,514 control chromosomes in the GnomAD database, including 3,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1521W) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.041 (225 hom., cov: 29)
  • Exomes 𝑓: 0.054 (3104 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0120

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018331409).
• BP6: Variant 15-43601535-C-T is Benign according to our data. Variant chr15-43601535-C-T is described in ClinVar as [Benign]. Clinvar id is 165304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43601535-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2	c.4562G>A	p.Arg1521Gln	missense_variant	24/29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.4562G>A	p.Arg1521Gln	missense_variant	24/29	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6249 AN: 151832 Hom.: 225 Cov.: 29

Gnomad AFR AF: 0.00990

Gnomad AMI AF: 0.0751

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0791

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0291

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0583

Gnomad OTH AF: 0.0461

GnomAD3 exomes AF: 0.0459 AC: 11537 AN: 251130 Hom.: 416 AF XY: 0.0471 AC XY: 6397 AN XY: 135796

Gnomad AFR exome AF: 0.00964

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0767

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0346

Gnomad FIN exome AF: 0.0704

Gnomad NFE exome AF: 0.0601

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0544 AC: 79437 AN: 1461564 Hom.: 3104 Cov.: 32 AF XY: 0.0540 AC XY: 39231 AN XY: 727100

Gnomad4 AFR exome AF: 0.00887

Gnomad4 AMR exome AF: 0.0272

Gnomad4 ASJ exome AF: 0.0750

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0371

Gnomad4 FIN exome AF: 0.0653

Gnomad4 NFE exome AF: 0.0590

Gnomad4 OTH exome AF: 0.0510

GnomAD4 genome AF: 0.0411 AC: 6248 AN: 151950 Hom.: 225 Cov.: 29 AF XY: 0.0419 AC XY: 3108 AN XY: 74246

Gnomad4 AFR AF: 0.00987

Gnomad4 AMR AF: 0.0301

Gnomad4 ASJ AF: 0.0791

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.0291

Gnomad4 FIN AF: 0.0758

Gnomad4 NFE AF: 0.0584

Gnomad4 OTH AF: 0.0456

Alfa AF: 0.0528 Hom.: 160

Bravo AF: 0.0365

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0576 AC: 222

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0606 AC: 521

ExAC AF: 0.0465 AC: 5645

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0593

EpiControl AF: 0.0577

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Arg1521Gln in Exon 24 of STRC: This variant is not expected to have clinical sig nificance because it has been identified in 6.0% (422/7018) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs74643365). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.16	N;N
REVEL	Benign	0.063
Sift	Benign	0.31	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0010	B;P
Vest4		0.20
ClinPred		0.0063	T
GERP RS		1.7
Varity_R		0.061
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs74643365; hg19: chr15-43893733;