15-43616655-G-T

Variant names:

• chr15-43616655-G-T
• rs727503448
• NM_153700.2:c.911C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_153700.2(STRC):​c.911C>A​(p.Ala304Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A304V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000058 (0 hom., cov: 10)
  • Exomes 𝑓: 0.00011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• 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

ENSG00000284772 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.09164804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.911C>A	p.Ala304Glu	missense_variant	Exon 4 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.911C>A	p.Ala304Glu	missense_variant	Exon 4 of 29	5	NM_153700.2	ENSP00000401513.2
ENSG00000284772	ENST00000643290.1	n.*1074C>A		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000495476.1
ENSG00000284772	ENST00000643290.1	n.*1074C>A		3_prime_UTR_variant	Exon 6 of 9			ENSP00000495476.1

Frequencies

GnomAD3 genomes AF: 0.0000578 AC: 5 AN: 86488 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000688

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000561 AC: 3 AN: 53470 AF XY: 0.0000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000964

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.0000500

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000114 AC: 49 AN: 429918 Hom.: 0 Cov.: 0 AF XY: 0.000119 AC XY: 27 AN XY: 226596

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

African (AFR) AF: 0.00 AC: 0 AN: 11648

American (AMR) AF: 0.0000551 AC: 1 AN: 18136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13232

East Asian (EAS) AF: 0.00 AC: 0 AN: 29822

South Asian (SAS) AF: 0.00 AC: 0 AN: 44716

European-Finnish (FIN) AF: 0.000797 AC: 22 AN: 27612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1858

European-Non Finnish (NFE) AF: 0.0000891 AC: 23 AN: 258032

Other (OTH) AF: 0.000121 AC: 3 AN: 24862

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000578 AC: 5 AN: 86570 Hom.: 0 Cov.: 10 AF XY: 0.000102 AC XY: 4 AN XY: 39406

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

African (AFR) AF: 0.00 AC: 0 AN: 18942

American (AMR) AF: 0.000121 AC: 1 AN: 8256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2404

East Asian (EAS) AF: 0.00 AC: 0 AN: 3218

South Asian (SAS) AF: 0.00 AC: 0 AN: 2102

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 246

European-Non Finnish (NFE) AF: 0.0000688 AC: 3 AN: 43600

Other (OTH) AF: 0.00 AC: 0 AN: 1060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	.;.
PhyloP100		2.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.89	N;D
REVEL	Uncertain	0.41
Sift	Benign	0.036	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.60
ClinPred		0.092	T
GERP RS		4.0
Varity_R		0.23
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs727503448; hg19: chr15-43908853;