rs199524735

Positions:

chr15-43609293-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_153700.2(STRC):c.3540T>G(p.Leu1180=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,608,722 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 23 hom., cov: 26)

Exomes 𝑓: 0.00076 ( 43 hom. )

Consequence

STRC
NM_153700.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.275

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 15-43609293-A-C is Benign according to our data. Variant chr15-43609293-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 227965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43609293-A-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.275 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0034 (511/150282) while in subpopulation AFR AF= 0.00737 (294/39892). AF 95% confidence interval is 0.00668. There are 23 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2 linkuse as main transcript	c.3540T>G	p.Leu1180=	synonymous_variant	16/29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 linkuse as main transcript	c.3540T>G	p.Leu1180=	synonymous_variant	16/29	5	NM_153700.2	ENSP00000401513	P2

Frequencies

GnomAD3 genomes

AF:

0.00341

AC:

512

AN:

150168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00742

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00664

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00237

Gnomad SAS

AF:

0.00606

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000868

Gnomad OTH

AF:

0.00434

GnomAD3 exomes

AF:

0.000859

AC:

215

AN:

250252

Hom.:

AF XY:

0.000857

AC XY:

116

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.000605

Gnomad SAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000762

AC:

1112

AN:

1458440

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

672

AN XY:

725552

show subpopulations

Gnomad4 AFR exome

AF:

0.00429

Gnomad4 AMR exome

AF:

0.00211

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.000763

Gnomad4 SAS exome

AF:

0.00396

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.000339

Gnomad4 OTH exome

AF:

0.000914

GnomAD4 genome

AF:

0.00340

AC:

511

AN:

150282

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

267

AN XY:

73478

show subpopulations

Gnomad4 AFR

AF:

0.00737

Gnomad4 AMR

AF:

0.00663

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00238

Gnomad4 SAS

AF:

0.00607

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000868

Gnomad4 OTH

AF:

0.00429

Alfa

AF:

0.00166

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The STRC p.Leu1180Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs199524735) and in ClinVar (classified as benign by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine). The variant was also identified in control databases in 284 of 281132 chromosomes (20 homozygous) at a frequency of 0.00101 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 98 of 24194 chromosomes (freq: 0.004051), South Asian in 58 of 30480 chromosomes (freq: 0.001903), Latino in 58 of 35362 chromosomes (freq: 0.00164), East Asian in 14 of 19680 chromosomes (freq: 0.000711), Other in 4 of 7204 chromosomes (freq: 0.000555), Ashkenazi Jewish in 5 of 10354 chromosomes (freq: 0.000483), European (non-Finnish) in 44 of 128746 chromosomes (freq: 0.000342), and European (Finnish) in 3 of 25112 chromosomes (freq: 0.00012). The p.Leu1180Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. Three in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) predict the loss of an unannotated 5' splice site, however the known canonical splice site is not predicted to be affected. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2017	p.Leu1180Leu in exon 16 of STRC: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and it has been identified in 0.4% (97/23254) African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs199524735). -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	STRC: BP4, BP7, BS2 -

Autosomal recessive nonsyndromic hearing loss 16

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

8.2

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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