rs199524735

Variant names:

• chr15-43609293-A-C
• rs199524735
• NM_153700.2:c.3540T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-43609293-A-C
• chr15-43609293-A-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_153700.2(STRC):​c.3540T>G​(p.Leu1180Leu) 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:7
• Conservation: PhyloP100: 0.275
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 227965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153700.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	NM_153700.2	MANE Select	c.3540T>G	p.Leu1180Leu	synonymous	Exon 16 of 29	NP_714544.1	Q7RTU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	ENST00000450892.7	TSL:5 MANE Select	c.3540T>G	p.Leu1180Leu	synonymous	Exon 16 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*1332T>G		non_coding_transcript_exon	Exon 15 of 28	ENSP00000394866.1	E7EPM8
	STRC	ENST00000440125.5	TSL:1	n.*1332T>G		3_prime_UTR	Exon 15 of 28	ENSP00000394866.1	E7EPM8

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

GnomAD2 exomes AF: 0.000859 AC: 215 AN: 250252 AF XY: 0.000857

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 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

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

African (AFR) AF: 0.00429 AC: 140 AN: 32622

American (AMR) AF: 0.00211 AC: 94 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26068

East Asian (EAS) AF: 0.000763 AC: 30 AN: 39344

South Asian (SAS) AF: 0.00396 AC: 340 AN: 85820

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53376

Middle Eastern (MID) AF: 0.00349 AC: 20 AN: 5736

European-Non Finnish (NFE) AF: 0.000339 AC: 377 AN: 1110694

Other (OTH) AF: 0.000914 AC: 55 AN: 60178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00340 AC: 511 AN: 150282 Hom.: 23 Cov.: 26 AF XY: 0.00363 AC XY: 267 AN XY: 73478

African (AFR) AF: 0.00737 AC: 294 AN: 39892

American (AMR) AF: 0.00663 AC: 101 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.00238 AC: 12 AN: 5050

South Asian (SAS) AF: 0.00607 AC: 29 AN: 4778

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 67960

Other (OTH) AF: 0.00429 AC: 9 AN: 2096

Alfa AF: 0.00166 Hom.: 3

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.2
DANN	Benign	0.80
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199524735; hg19: chr15-43901491;