rs199524735

chr15-43609293-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.275

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]

ACMG classification

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 GnomAd at 23 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 512 AN: 150168 Hom.: 23 Cov.: 26

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.: 15 AF XY: 0.000857 AC XY: 116 AN XY: 135300

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.: 43 Cov.: 31 AF XY: 0.000926 AC XY: 672 AN XY: 725552

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.: 23 Cov.: 26 AF XY: 0.00363 AC XY: 267 AN XY: 73478

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.: 3

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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). -
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. -

not provided Benign:1

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

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- -

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

Other links and lift over

dbSNP: rs199524735; hg19: chr15-43901491;