rs150415498

Variant names:

• chr16-21716940-G-A
• rs150415498
• NM_144672.4:c.1522G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-21716940-G-A
• chr16-21716940-G-C
• chr16-21716940-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144672.4(OTOA):​c.1522G>A​(p.Val508Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,006 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V508A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (11 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.370
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005751699).
• BP6: Variant 16-21716940-G-A is Benign according to our data. Variant chr16-21716940-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00188 (286/152156) while in subpopulation NFE AF = 0.00278 (189/68022). AF 95% confidence interval is 0.00245. There are 2 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1522G>A	p.Val508Met	missense	Exon 15 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.1285G>A	p.Val429Met	missense	Exon 10 of 24	NP_001155155.1	Q7RTW8-4
	OTOA	NM_170664.3		c.550G>A	p.Val184Met	missense	Exon 5 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.1522G>A	p.Val508Met	missense	Exon 15 of 29	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.1522G>A	p.Val508Met	missense	Exon 14 of 28	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.1564G>A	p.Val522Met	missense	Exon 14 of 28	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00586

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00218 AC: 547 AN: 251320 AF XY: 0.00218

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00540

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00220 AC: 3218 AN: 1461850 Hom.: 11 Cov.: 32 AF XY: 0.00220 AC XY: 1599 AN XY: 727234

African (AFR) AF: 0.000418 AC: 14 AN: 33478

American (AMR) AF: 0.000537 AC: 24 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00558 AC: 298 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00247 AC: 2749 AN: 1111978

Other (OTH) AF: 0.00152 AC: 92 AN: 60394

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152156 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74378

African (AFR) AF: 0.000650 AC: 27 AN: 41524

American (AMR) AF: 0.000393 AC: 6 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00586 AC: 62 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00278 AC: 189 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00260 Hom.: 2

Bravo AF: 0.00141

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00245

EpiControl AF: 0.00225

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	-	1	not specified (1)
-	-	1	OTOA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.37
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.063
Sift	Benign	0.19	T
Sift4G	Benign	0.20	T
Polyphen		0.18	B
Vest4		0.13
MVP		0.50
MPC		0.18
ClinPred		0.0044	T
GERP RS		1.8
Varity_R		0.041
gMVP		0.074
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150415498; hg19: chr16-21728261;