15-43610999-GT-GTT

Variant names:

• chr15-43610999-G-GT
• rs727503445
• NM_153700.2:c.3307-16dupA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_153700.2(STRC):​c.3307-16dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 75,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.213
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 15-43610999-G-GT is Benign according to our data. Variant chr15-43610999-G-GT is described in ClinVar as [Benign]. Clinvar id is 165316.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.3307-16dupA		intron_variant	Intron 13 of 28	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.3307-16dupA		intron_variant	Intron 13 of 28	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 93 AN: 75744 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000487

Gnomad ASJ AF: 0.0318

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000816

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000587

Gnomad OTH AF: 0.00372

GnomAD2 exomes AF: 0.00380 AC: 876 AN: 230240 AF XY: 0.00452

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.00974

Gnomad EAS exome AF: 0.0000568

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00390

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000165 AC: 199 AN: 1202544 Hom.: 0 Cov.: 61 AF XY: 0.000156 AC XY: 94 AN XY: 601964

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

African (AFR) AF: 0.0000908 AC: 2 AN: 22026

American (AMR) AF: 0.000115 AC: 4 AN: 34868

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 81 AN: 20352

East Asian (EAS) AF: 0.00 AC: 0 AN: 36064

South Asian (SAS) AF: 0.000197 AC: 14 AN: 70956

European-Finnish (FIN) AF: 0.0000797 AC: 4 AN: 50210

Middle Eastern (MID) AF: 0.000214 AC: 1 AN: 4682

European-Non Finnish (NFE) AF: 0.0000810 AC: 74 AN: 913496

Other (OTH) AF: 0.000381 AC: 19 AN: 49890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00121 AC: 92 AN: 75778 Hom.: 0 Cov.: 23 AF XY: 0.00112 AC XY: 42 AN XY: 37658

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

African (AFR) AF: 0.000407 AC: 4 AN: 9822

American (AMR) AF: 0.000486 AC: 4 AN: 8234

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 55 AN: 1732

East Asian (EAS) AF: 0.00 AC: 0 AN: 3150

South Asian (SAS) AF: 0.000815 AC: 2 AN: 2454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 132

European-Non Finnish (NFE) AF: 0.000562 AC: 23 AN: 40920

Other (OTH) AF: 0.00368 AC: 4 AN: 1088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00427 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In 20 validation samples, this variant was detected twice by NGS. Sanger confir mation has not been attempted. This variant may represent a sequencing artifac t, given it's presence in a string of "CA" repeats, or it may be a true variant. Given the frequency of this variant during validation, we have classified it a s Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs727503445; hg19: chr15-43903197;