rs215901

chr16-21719128-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144672.4(OTOA):c.1630-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,611,852 control chromosomes in the GnomAD database, including 347,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30277 hom., cov: 32)
  • Exomes 𝑓: 0.66 (317426 hom.)
• Consequence: OTOA NM_144672.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009088
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.457

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-21719128-C-T is Benign according to our data. Variant chr16-21719128-C-T is described in ClinVar as [Benign]. Clinvar id is 47952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21719128-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.1630-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.1630-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_144672.4	P2

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95438 AN: 151912 Hom.: 30259 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.635

GnomAD3 exomes AF: 0.625 AC: 156782 AN: 250836 Hom.: 49814 AF XY: 0.636 AC XY: 86180 AN XY: 135558

Gnomad AFR exome AF: 0.583

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.656

Gnomad EAS exome AF: 0.504

Gnomad SAS exome AF: 0.663

Gnomad FIN exome AF: 0.637

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.644

GnomAD4 exome AF: 0.657 AC: 959542 AN: 1459822 Hom.: 317426 Cov.: 45 AF XY: 0.659 AC XY: 478791 AN XY: 726286

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.649

Gnomad4 EAS exome AF: 0.525

Gnomad4 SAS exome AF: 0.668

Gnomad4 FIN exome AF: 0.642

Gnomad4 NFE exome AF: 0.671

Gnomad4 OTH exome AF: 0.644

GnomAD4 genome AF: 0.628 AC: 95490 AN: 152030 Hom.: 30277 Cov.: 32 AF XY: 0.625 AC XY: 46485 AN XY: 74338

Gnomad4 AFR AF: 0.580

Gnomad4 AMR AF: 0.566

Gnomad4 ASJ AF: 0.645

Gnomad4 EAS AF: 0.509

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.636

Alfa AF: 0.666 Hom.: 54334

Bravo AF: 0.621

Asia WGS AF: 0.577 AC: 2010 AN: 3478

EpiCase AF: 0.676

EpiControl AF: 0.682

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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	May 07, 2012	1630-5C>T in Intron 14 of OTOA: This variant is not expected to have clinical si gnificance because it has been identified in 40.7% (1520/3738) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs215901). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Autosomal recessive nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	11
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000091
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs215901; hg19: chr16-21730449; COSMIC: COSV53751279;