rs727503449

Variant names:

• chr15-43611236-C-T
• rs727503449
• NM_153700.2:c.3218G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153700.2(STRC):​c.3218G>A​(p.Arg1073Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 15)
  • Exomes 𝑓: 0.00068 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 1.03
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008996576).

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.3218G>A	p.Arg1073Gln	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.3218G>A	p.Arg1073Gln	missense	Exon 13 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*1215+263G>A		intron	N/A	ENSP00000394866.1	E7EPM8
	STRC	ENST00000541030.5	TSL:5	c.1104+263G>A		intron	N/A	ENSP00000440413.1	F5GXA4

Frequencies

GnomAD3 genomes AF: 0.000435 AC: 53 AN: 121748 Hom.: 1 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000172

Gnomad ASJ AF: 0.00287

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0179

Gnomad NFE AF: 0.000689

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000854 AC: 83 AN: 97148 AF XY: 0.000848

Gnomad AFR exome AF: 0.000320

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000988

Gnomad OTH exome AF: 0.00222

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000676 AC: 495 AN: 732056 Hom.: 11 Cov.: 10 AF XY: 0.000701 AC XY: 265 AN XY: 378236

African (AFR) AF: 0.000324 AC: 7 AN: 21574

American (AMR) AF: 0.00120 AC: 40 AN: 33218

Ashkenazi Jewish (ASJ) AF: 0.00216 AC: 41 AN: 18964

East Asian (EAS) AF: 0.0000305 AC: 1 AN: 32766

South Asian (SAS) AF: 0.000370 AC: 23 AN: 62100

European-Finnish (FIN) AF: 0.0000615 AC: 2 AN: 32530

Middle Eastern (MID) AF: 0.00695 AC: 19 AN: 2732

European-Non Finnish (NFE) AF: 0.000673 AC: 331 AN: 491954

Other (OTH) AF: 0.000856 AC: 31 AN: 36218

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000427 AC: 52 AN: 121864 Hom.: 1 Cov.: 15 AF XY: 0.000380 AC XY: 22 AN XY: 57840

African (AFR) AF: 0.00 AC: 0 AN: 35010

American (AMR) AF: 0.000172 AC: 2 AN: 11646

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 8 AN: 2792

East Asian (EAS) AF: 0.00 AC: 0 AN: 4098

South Asian (SAS) AF: 0.00 AC: 0 AN: 3118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7496

Middle Eastern (MID) AF: 0.0155 AC: 4 AN: 258

European-Non Finnish (NFE) AF: 0.000689 AC: 38 AN: 55184

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00103 Hom.: 0

ExAC AF: 0.000269 AC: 18

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	2	-	Autosomal recessive nonsyndromic hearing loss 16 (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.86	T
PhyloP100		1.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.12
Sift	Benign	0.22	T
Sift4G	Benign	0.088	T
Polyphen		0.61	P
Vest4		0.12
MutPred		0.34		Gain of catalytic residue at R1073 (P = 0.0753)
MVP		0.47
ClinPred		0.0059	T
GERP RS		3.2
Varity_R		0.068
gMVP		0.27
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs727503449; hg19: chr15-43903434;