rs464696

Variant names:

• chr16-21736312-A-C
• rs464696
• NM_144672.4:c.2353A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-21736312-A-C
• chr16-21736312-A-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_144672.4(OTOA):​c.2353A>C​(p.Thr785Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,567,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (0 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.17

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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033976436).
• BP6: Variant 16-21736312-A-C is Benign according to our data. Variant chr16-21736312-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218840.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chr16-21736312-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.2353A>C	p.Thr785Pro	missense_variant	Exon 22 of 29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.2353A>C	p.Thr785Pro	missense_variant	Exon 22 of 29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1348 AN: 146512 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.00177

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0107

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.000528 AC: 129 AN: 244372 AF XY: 0.000423

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00271 AC: 3856 AN: 1421226 Hom.: 0 Cov.: 32 AF XY: 0.00266 AC XY: 1885 AN XY: 707592

Gnomad4 AFR exome AF: 0.000180 AC: 6 AN: 33346

Gnomad4 AMR exome AF: 0.0153 AC: 532 AN: 34816

Gnomad4 ASJ exome AF: 0.000506 AC: 13 AN: 25680

Gnomad4 EAS exome AF: 0.109 AC: 2644 AN: 24186

Gnomad4 SAS exome AF: 0.000240 AC: 20 AN: 83236

Gnomad4 FIN exome AF: 0.00516 AC: 250 AN: 48444

Gnomad4 NFE exome AF: 0.000216 AC: 239 AN: 1107898

Gnomad4 Remaining exome AF: 0.00259 AC: 150 AN: 57928

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

GnomAD4 genome AF: 0.00928 AC: 1360 AN: 146628 Hom.: 0 Cov.: 32 AF XY: 0.0108 AC XY: 769 AN XY: 71166

Gnomad4 AFR AF: 0.00158 AC: 0.00157652 AN: 0.00157652

Gnomad4 AMR AF: 0.0358 AC: 0.0358047 AN: 0.0358047

Gnomad4 ASJ AF: 0.00177 AC: 0.00176574 AN: 0.00176574

Gnomad4 EAS AF: 0.112 AC: 0.112285 AN: 0.112285

Gnomad4 SAS AF: 0.0105 AC: 0.0104941 AN: 0.0104941

Gnomad4 FIN AF: 0.0247 AC: 0.0246669 AN: 0.0246669

Gnomad4 NFE AF: 0.00138 AC: 0.00137611 AN: 0.00137611

Gnomad4 OTH AF: 0.0130 AC: 0.013 AN: 0.013

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

Alfa AF: 0.00442 Hom.: 0

ExAC AF: 0.00226 AC: 274

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Oct 31, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr785Pro variant in OTOA is classified as benign because it has been iden tified in 0.9% (139/15388) of East Asian chromosomes by gnomAD (http://gnomad.br oadinstitute.org). Furthermore, the threonine (Thr) at this position is not cons erved across species. Over 10 mammals carry a proline (Pro) at this position. -

OTOA-related disorder Uncertain:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The OTOA c.2353A>C variant is predicted to result in the amino acid substitution p.Thr785Pro. This variant was reported along with a second potentially pathogenic variant in four individuals with auditory neuropathy and was classified as uncertain (Table S8, Song et al. 2021. PubMed ID: 34175691). This variant is reported in 0.84% of alleles in individuals of East Asian descent in gnomAD. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive nonsyndromic hearing loss 22 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.095
DEOGEN2	Benign	0.012	.;T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00036	N
LIST_S2	Benign	0.20	.;T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	.;N;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.2	.;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	1.0	.;T;T;T;T
Sift4G	Benign	1.0	.;T;T;T;T
Polyphen		0.0	.;B;.;.;B
Vest4		0.11, 0.11, 0.13, 0.11
MVP		0.22
MPC		0.22
ClinPred		0.011	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.30
Mutation Taster		=93/7	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

Publications

LitVar

Other links and lift over

dbSNP: rs464696; hg19: chr16-21747633; COSMIC: COSV53748541;