16-21678250-A-T

Variant names:

• chr16-21678250-A-T
• rs118052093
• NM_144672.4:c.-4-261A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_144672.4(OTOA):​c.-4-261A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 152,100 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.023 (76 hom., cov: 31)
• Consequence: OTOA NM_144672.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0630
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-21678250-A-T is Benign according to our data. Variant chr16-21678250-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1205134.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0235 (3567/152100) while in subpopulation NFE AF = 0.0359 (2442/67994). AF 95% confidence interval is 0.0347. There are 76 homozygotes in GnomAd4. There are 1662 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.-4-261A>T		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.-4-261A>T		intron_variant	Intron 1 of 28		NM_144672.4	ENSP00000496564.2
OTOA	ENST00000647277.1	n.-4-261A>T		intron_variant	Intron 1 of 28			ENSP00000495594.1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3568 AN: 151982 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.00522

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0192

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0235 AC: 3567 AN: 152100 Hom.: 76 Cov.: 31 AF XY: 0.0224 AC XY: 1662 AN XY: 74352

African (AFR) AF: 0.00520 AC: 216 AN: 41520

American (AMR) AF: 0.0150 AC: 228 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4818

European-Finnish (FIN) AF: 0.0297 AC: 314 AN: 10580

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0359 AC: 2442 AN: 67994

Other (OTH) AF: 0.0190 AC: 40 AN: 2108

Alfa AF: 0.0129 Hom.: 6

Bravo AF: 0.0223

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.8
DANN	Benign	0.76
PhyloP100		0.063
PromoterAI		-0.022	Neutral

Splicing

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

Other links and lift over

dbSNP: rs118052093; hg19: chr16-21689571;