rs215894

Variant names:

• chr16-21678470-T-A
• rs215894
• NM_144672.4:c.-4-41T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144672.4(OTOA):​c.-4-41T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,180,340 control chromosomes in the GnomAD database, including 72,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8726 hom., cov: 30)
  • Exomes 𝑓: 0.37 (63869 hom.)
• Consequence: OTOA NM_144672.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.340
• Publications: 8 publications found

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]

OTOA Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 22

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-21678470-T-A is Benign according to our data. Variant chr16-21678470-T-A is described in ClinVar as [Benign]. Clinvar id is 1287638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.-4-41T>A		intron_variant	Intron 1 of 28	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.-4-41T>A		intron_variant	Intron 1 of 28		NM_144672.4	ENSP00000496564.2
OTOA	ENST00000647277.1	n.-4-41T>A		intron_variant	Intron 1 of 28			ENSP00000495594.1
OTOA	ENST00000388958.8	c.-45T>A		upstream_gene_variant		1		ENSP00000373610.3
OTOA	ENST00000286149.8	c.-45T>A		upstream_gene_variant		5		ENSP00000286149.4

Frequencies

GnomAD3 genomes AF: 0.315 AC: 46981 AN: 149274 Hom.: 8723 Cov.: 30

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.319

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.314 AC: 65489 AN: 208754 AF XY: 0.321

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.367

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.369 AC: 380202 AN: 1030970 Hom.: 63869 Cov.: 13 AF XY: 0.371 AC XY: 196006 AN XY: 528140

African (AFR) AF: 0.0995 AC: 2427 AN: 24392

American (AMR) AF: 0.297 AC: 11918 AN: 40150

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 7749 AN: 22770

East Asian (EAS) AF: 0.100 AC: 3384 AN: 33800

South Asian (SAS) AF: 0.387 AC: 28505 AN: 73606

European-Finnish (FIN) AF: 0.344 AC: 16980 AN: 49340

Middle Eastern (MID) AF: 0.349 AC: 1274 AN: 3654

European-Non Finnish (NFE) AF: 0.396 AC: 292367 AN: 737960

Other (OTH) AF: 0.344 AC: 15598 AN: 45298

GnomAD4 genome AF: 0.315 AC: 46983 AN: 149370 Hom.: 8726 Cov.: 30 AF XY: 0.311 AC XY: 22703 AN XY: 72920

African (AFR) AF: 0.114 AC: 4575 AN: 39974

American (AMR) AF: 0.315 AC: 4703 AN: 14926

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1269 AN: 3440

East Asian (EAS) AF: 0.116 AC: 573 AN: 4946

South Asian (SAS) AF: 0.417 AC: 1998 AN: 4790

European-Finnish (FIN) AF: 0.376 AC: 3879 AN: 10306

Middle Eastern (MID) AF: 0.329 AC: 94 AN: 286

European-Non Finnish (NFE) AF: 0.426 AC: 28815 AN: 67716

Other (OTH) AF: 0.338 AC: 700 AN: 2074

Alfa AF: 0.360 Hom.: 1782

Bravo AF: 0.301

Asia WGS AF: 0.261 AC: 908 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.24
PhyloP100		-0.34
PromoterAI		0.0019	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs215894; hg19: chr16-21689791; COSMIC: COSV53762254; COSMIC: COSV53762254;