rs1555447608

Variant names:

• chr15-43615990-G-A
• rs1555447608
• NM_153700.2:c.1576C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_153700.2(STRC):​c.1576C>T​(p.Arg526Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.00026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32393909).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.1576C>T	p.Arg526Cys	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.1576C>T	p.Arg526Cys	missense_variant	Exon 4 of 29	5	NM_153700.2	ENSP00000401513.2
ENSG00000284772	ENST00000643290.1	n.*1218-421C>T		intron_variant	Intron 6 of 8			ENSP00000495476.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000259 AC: 1 AN: 3866 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1954

⚠️ 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: 10

American (AMR) AF: 0.00 AC: 0 AN: 1004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 68

South Asian (SAS) AF: 0.00307 AC: 1 AN: 326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2320

Other (OTH) AF: 0.00 AC: 0 AN: 128

⚠️ 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 Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 16 Uncertain:1

Dec 11, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.75	T
PhyloP100		2.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.051	B;.
Vest4		0.45
MutPred		0.46		Loss of disorder (P = 0.0471);.;
MVP		0.80
ClinPred		0.79	D
GERP RS		3.4
Varity_R		0.25
gMVP		0.56
Mutation Taster		=75/25	polymorphism

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: rs1555447608; hg19: chr15-43908188;