Variant rs727503449 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153700.2(STRC):c.3218G>A(p.Arg1073Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 15)

Exomes 𝑓: 0.00068 ( 11 hom. )

Failed GnomAD Quality Control

Consequence

STRC
NM_153700.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.03

Variant links:

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 links:

STRC (HGNC:):

STRC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008996576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2 linkuse as main transcript	c.3218G>A	p.Arg1073Gln	missense_variant	13/29	ENST00000450892.7	NP_714544.1	Q7RTU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 linkuse as main transcript	c.3218G>A	p.Arg1073Gln	missense_variant	13/29	5	NM_153700.2	ENSP00000401513.2		Q7RTU9

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

121748

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000172

Gnomad ASJ

AF:

0.00287

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0179

Gnomad NFE

AF:

0.000689

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000854

AC:

AN:

97148

Hom.:

AF XY:

0.000848

AC XY:

AN XY:

50698

show subpopulations

Gnomad AFR exome

AF:

0.000320

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000142

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000988

Gnomad OTH exome

AF:

0.00222

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000676

AC:

495

AN:

732056

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

265

AN XY:

378236

show subpopulations

Gnomad4 AFR exome

AF:

0.000324

Gnomad4 AMR exome

AF:

0.00120

Gnomad4 ASJ exome

AF:

0.00216

Gnomad4 EAS exome

AF:

0.0000305

Gnomad4 SAS exome

AF:

0.000370

Gnomad4 FIN exome

AF:

0.0000615

Gnomad4 NFE exome

AF:

0.000673

Gnomad4 OTH exome

AF:

0.000856

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000427

AC:

AN:

121864

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

AN XY:

57840

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000172

Gnomad4 ASJ

AF:

0.00287

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000689

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00103

Hom.:

ExAC

AF:

0.000269

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32860223) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 28, 2022	BS1_supporting, BP4, PM3 -

Autosomal recessive nonsyndromic hearing loss 16

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 25, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1073Gln va riant in STRC has been previously reported in three individuals with hearing los s (LMM unpublished data), one of whom had a pathogenic variant and the p.Cys1092 Tyr variant of uncertain significance in STRC; however, the cis/trans configurat ion of the variants was not determined. A second STRC variant was not detected i n the other two individuals (LMM unpublished data). This variant has been identi fied in 0.5% (4/888) of European chromosomes and in 0.4% (2/492) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs727503449); however, this allele frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal yses suggest that the variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. In summary, while the clin ical significance of the p.Arg1073Gln variant is uncertain, the population frequ ency data suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.034

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.013

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.86

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.060

REVEL

Benign

0.12

Sift

Benign

0.22

Sift4G

Benign

0.088

Polyphen

0.61

Vest4

0.12

MutPred

0.34

Gain of catalytic residue at R1073 (P = 0.0753);

MVP

0.47

ClinPred

0.0059

GERP RS

3.2

Varity_R

0.068

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over