rs139312489

Variant names:

• chr16-21730858-C-T
• rs461179
• NM_144672.4:c.2229C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-21730858-C-T
• chrNW_017852933.1-1373948-G-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_144672.4(OTOA):​c.2229C>T​(p.Ala743Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 141,714 control chromosomes in the GnomAD database, including 1,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1123 hom., cov: 30)
  • Exomes 𝑓: 0.030 (5452 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.31
• Publications: 6 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, 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-21730858-C-T is Benign according to our data. Variant chr16-21730858-C-T is described in ClinVar as Benign. ClinVar VariationId is 164827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 1123 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144672.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	NM_144672.4	MANE Select	c.2229C>T	p.Ala743Ala	synonymous	Exon 21 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.1992C>T	p.Ala664Ala	synonymous	Exon 16 of 24	NP_001155155.1	Q7RTW8-4
	OTOA	NM_170664.3		c.1257C>T	p.Ala419Ala	synonymous	Exon 11 of 19	NP_733764.1	Q7RTW8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	ENST00000646100.2	MANE Select	c.2229C>T	p.Ala743Ala	synonymous	Exon 21 of 29	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.2229C>T	p.Ala743Ala	synonymous	Exon 20 of 28	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.2271C>T	p.Ala757Ala	synonymous	Exon 20 of 28	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 14999 AN: 141612 Hom.: 1116 Cov.: 30

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.0738

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.157

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.0305 AC: 7072 AN: 232152 AF XY: 0.0293

Gnomad AFR exome AF: 0.00931

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.0932

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0386

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0295 AC: 39417 AN: 1334280 Hom.: 5452 Cov.: 29 AF XY: 0.0322 AC XY: 21326 AN XY: 661458

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

African (AFR) AF: 0.0100 AC: 328 AN: 32716

American (AMR) AF: 0.0414 AC: 1664 AN: 40218

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1457 AN: 22926

East Asian (EAS) AF: 0.111 AC: 3516 AN: 31668

South Asian (SAS) AF: 0.0881 AC: 6114 AN: 69382

European-Finnish (FIN) AF: 0.0702 AC: 3232 AN: 46072

Middle Eastern (MID) AF: 0.0438 AC: 224 AN: 5116

European-Non Finnish (NFE) AF: 0.0200 AC: 20628 AN: 1031850

Other (OTH) AF: 0.0415 AC: 2254 AN: 54332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.106 AC: 15010 AN: 141714 Hom.: 1123 Cov.: 30 AF XY: 0.110 AC XY: 7556 AN XY: 68698

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

African (AFR) AF: 0.0351 AC: 1425 AN: 40550

American (AMR) AF: 0.128 AC: 1786 AN: 13926

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 548 AN: 3184

East Asian (EAS) AF: 0.231 AC: 1013 AN: 4380

South Asian (SAS) AF: 0.220 AC: 918 AN: 4170

European-Finnish (FIN) AF: 0.158 AC: 1431 AN: 9082

Middle Eastern (MID) AF: 0.147 AC: 38 AN: 258

European-Non Finnish (NFE) AF: 0.120 AC: 7570 AN: 63312

Other (OTH) AF: 0.110 AC: 215 AN: 1958

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.115 Hom.: 278

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.070
DANN	Benign	0.76
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs461179; hg19: chr16-21742179; COSMIC: COSV53748363;