rs138141474

Variant names:

• chr16-21716941-T-C
• rs138141474
• NM_144672.4:c.1523T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_144672.4(OTOA):​c.1523T>C​(p.Val508Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000774 in 1,614,072 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V508M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00097 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.843
• Publications: 9 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050311983).
• BP6: Variant 16-21716941-T-C is Benign according to our data. Variant chr16-21716941-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178499.
• 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.1523T>C	p.Val508Ala	missense	Exon 15 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.1286T>C	p.Val429Ala	missense	Exon 10 of 24	NP_001155155.1	Q7RTW8-4
	OTOA	NM_170664.3		c.551T>C	p.Val184Ala	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.1523T>C	p.Val508Ala	missense	Exon 15 of 29	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.1523T>C	p.Val508Ala	missense	Exon 14 of 28	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.1565T>C	p.Val522Ala	missense	Exon 14 of 28	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152102 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00101 AC: 253 AN: 251322 AF XY: 0.00105

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000753 AC: 1101 AN: 1461850 Hom.: 1 Cov.: 32 AF XY: 0.000762 AC XY: 554 AN XY: 727232

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 353 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000480 AC: 534 AN: 1111976

Other (OTH) AF: 0.00205 AC: 124 AN: 60394

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74444

African (AFR) AF: 0.000313 AC: 13 AN: 41552

American (AMR) AF: 0.00262 AC: 40 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68030

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00112 Hom.: 2

Bravo AF: 0.00114

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000848 AC: 103

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive nonsyndromic hearing loss 22 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	OTOA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.96
DANN	Benign	0.44
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.84
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.098
Sift	Benign	0.78	T
Sift4G	Benign	0.76	T
Polyphen		0.0010	B
Vest4		0.078
MVP		0.47
MPC		0.20
ClinPred		0.0012	T
GERP RS		1.8
Varity_R		0.032
gMVP		0.063
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs138141474; hg19: chr16-21728262;