rs377581131

chr16-21709924-C-Gchr16-21709924-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_144672.4(OTOA):c.1141C>G(p.Gln381Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,614,030 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (73 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:4
• Conservation: PhyloP100: 4.07

Genes affected

OTOA (HGNC:16378): (otoancorin) The protein encoded by this gene is specifically expressed in the inner ear, and is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels. It is prposed that this protein is involved in the attachment of the inner ear acellular gels to the apical surface of the underlying nonsensory cells. Mutations in this gene are associated with autosomal recessive deafness type 22 (DFNB22). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036770701).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00119 (181/152220) while in subpopulation SAS AF= 0.0361 (174/4822). AF 95% confidence interval is 0.0317. There are 5 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.1141C>G	p.Gln381Glu	missense_variant	13/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.1141C>G	p.Gln381Glu	missense_variant	13/29		NM_144672.4	P2

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152102 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0365

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00424 AC: 1066 AN: 251360 Hom.: 22 AF XY: 0.00584 AC XY: 794 AN XY: 135846

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00211 AC: 3088 AN: 1461810 Hom.: 73 Cov.: 31 AF XY: 0.00314 AC XY: 2287 AN XY: 727212

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0340

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152220 Hom.: 5 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74436

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0361

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000215

ExAC AF: 0.00468 AC: 568

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 23, 2015	p.Gln381Glu in exon 12 of OTOA: This variant is not expected to have clinical si gnificance because it has been identified in 3.4% (558/16510) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs377581131). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2018	This variant is associated with the following publications: (PMID: 23173898) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Dec 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0037	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.40	T
Polyphen		0.87, 0.63	.;P;.;.;P
Vest4		0.36, 0.36, 0.35, 0.43
MutPred		0.23		.;Gain of helix (P = 0.0696);.;.;.;
MVP		0.54
MPC		0.46
ClinPred		0.044	T
GERP RS		5.2
Varity_R		0.19
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs377581131; hg19: chr16-21721245;