rs727503447

Variant names:

• chr15-43611179-C-T
• rs727503447
• NM_153700.2:c.3275G>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.3275G>A​(p.Cys1092Tyr) 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: 𝑓 0.000064 (0 hom., cov: 16)
  • Exomes 𝑓: 0.000062 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.68
• 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

ENSG00000309475 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.07783142).

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.3275G>A	p.Cys1092Tyr	missense	Exon 13 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.3275G>A	p.Cys1092Tyr	missense	Exon 13 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*1215+320G>A		intron	N/A	ENSP00000394866.1	E7EPM8
	STRC	ENST00000541030.5	TSL:5	c.1104+320G>A		intron	N/A	ENSP00000440413.1	F5GXA4

Frequencies

GnomAD3 genomes AF: 0.0000638 AC: 8 AN: 125326 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000842

Gnomad ASJ AF: 0.00242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000236 AC: 31 AN: 131144 AF XY: 0.000213

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000498

Gnomad ASJ exome AF: 0.00196

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000598

Gnomad OTH exome AF: 0.000767

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000622 AC: 75 AN: 1206000 Hom.: 3 Cov.: 18 AF XY: 0.0000546 AC XY: 33 AN XY: 604334

African (AFR) AF: 0.00 AC: 0 AN: 30882

American (AMR) AF: 0.000355 AC: 13 AN: 36574

Ashkenazi Jewish (ASJ) AF: 0.00181 AC: 42 AN: 23174

East Asian (EAS) AF: 0.00 AC: 0 AN: 36940

South Asian (SAS) AF: 0.00 AC: 0 AN: 77568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3710

European-Non Finnish (NFE) AF: 0.0000122 AC: 11 AN: 903662

Other (OTH) AF: 0.000173 AC: 9 AN: 51932

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000638 AC: 8 AN: 125326 Hom.: 0 Cov.: 16 AF XY: 0.0000837 AC XY: 5 AN XY: 59752

African (AFR) AF: 0.00 AC: 0 AN: 36596

American (AMR) AF: 0.0000842 AC: 1 AN: 11880

Ashkenazi Jewish (ASJ) AF: 0.00242 AC: 7 AN: 2888

East Asian (EAS) AF: 0.00 AC: 0 AN: 4044

South Asian (SAS) AF: 0.00 AC: 0 AN: 3388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56342

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000432 Hom.: 1

ExAC AF: 0.0000753 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive nonsyndromic hearing loss 16 (2)
-	2	-	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7 (1)
-	1	-	not specified (1)
-	1	-	STRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.81	T
PhyloP100		1.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.36	B
Vest4		0.52
MutPred		0.28		Loss of stability (P = 0.0719)
MVP		0.56
ClinPred		0.054	T
GERP RS		2.1
Varity_R		0.20
gMVP		0.47
Mutation Taster		=28/72	disease causing

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: rs727503447; hg19: chr15-43903377;