chr16-21678454-G-A

Variant names:

• chr16-21678454-G-A
• rs77996753
• NM_144672.4:c.-4-57G>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.-4-57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 861,546 control chromosomes in the GnomAD database, including 1,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (451 hom., cov: 31)
  • Exomes 𝑓: 0.025 (1339 hom.)
• Consequence: OTOA NM_144672.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.793
• Publications: 4 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=-0.91).
• BP6: Variant 16-21678454-G-A is Benign according to our data. Variant chr16-21678454-G-A is described in ClinVar as [Benign]. Clinvar id is 1259589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.-4-57G>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.-4-57G>A		intron_variant	Intron 1 of 28		NM_144672.4	ENSP00000496564.2
OTOA	ENST00000647277.1	n.-4-57G>A		intron_variant	Intron 1 of 28			ENSP00000495594.1
OTOA	ENST00000388958.8	c.-61G>A		upstream_gene_variant		1		ENSP00000373610.3
OTOA	ENST00000286149.8	c.-61G>A		upstream_gene_variant		5		ENSP00000286149.4

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7466 AN: 149466 Hom.: 448 Cov.: 31

Gnomad AFR AF: 0.0798

Gnomad AMI AF: 0.00771

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.00954

Gnomad MID AF: 0.0194

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.0564

GnomAD4 exome AF: 0.0249 AC: 17723 AN: 712018 Hom.: 1339 AF XY: 0.0248 AC XY: 9239 AN XY: 372786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0482 AC: 805 AN: 16692

American (AMR) AF: 0.137 AC: 4021 AN: 29270

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 422 AN: 18782

East Asian (EAS) AF: 0.260 AC: 6539 AN: 25108

South Asian (SAS) AF: 0.0270 AC: 1642 AN: 60730

European-Finnish (FIN) AF: 0.00970 AC: 406 AN: 41842

Middle Eastern (MID) AF: 0.0260 AC: 65 AN: 2502

European-Non Finnish (NFE) AF: 0.00606 AC: 2931 AN: 483464

Other (OTH) AF: 0.0265 AC: 892 AN: 33628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0500 AC: 7475 AN: 149528 Hom.: 451 Cov.: 31 AF XY: 0.0519 AC XY: 3785 AN XY: 72888

African (AFR) AF: 0.0799 AC: 3254 AN: 40712

American (AMR) AF: 0.114 AC: 1691 AN: 14848

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 112 AN: 3442

East Asian (EAS) AF: 0.262 AC: 1326 AN: 5064

South Asian (SAS) AF: 0.0496 AC: 235 AN: 4738

European-Finnish (FIN) AF: 0.00954 AC: 95 AN: 9958

Middle Eastern (MID) AF: 0.0176 AC: 5 AN: 284

European-Non Finnish (NFE) AF: 0.00942 AC: 636 AN: 67498

Other (OTH) AF: 0.0549 AC: 114 AN: 2076

Alfa AF: 0.0329 Hom.: 37

Bravo AF: 0.0658

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

- -

Aug 15, 2019

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	-0.91
CADD	Benign	1.4
DANN	Benign	0.16
PhyloP100		-0.79
PromoterAI		0.0062	Neutral

Splicing

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

Other links and lift over

dbSNP: rs77996753; hg19: chr16-21689775; COSMIC: COSV53752342; COSMIC: COSV53752342;