NM_144672.4:c.615C>T

Variant names:

• chr16-21687628-C-T
• rs16972658
• NM_144672.4:c.615C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144672.4(OTOA):​c.615C>T​(p.Arg205Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 1,611,076 control chromosomes in the GnomAD database, including 1,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (105 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1101 hom.)
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.63
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 16-21687628-C-T is Benign according to our data. Variant chr16-21687628-C-T is described in ClinVar as Benign. ClinVar VariationId is 47955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.63 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

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.615C>T	p.Arg205Arg	synonymous	Exon 8 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.378C>T	p.Arg126Arg	synonymous	Exon 3 of 24	NP_001155155.1	Q7RTW8-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	ENST00000646100.2	MANE Select	c.615C>T	p.Arg205Arg	synonymous	Exon 8 of 29	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.615C>T	p.Arg205Arg	synonymous	Exon 7 of 28	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.615C>T	p.Arg205Arg	synonymous	Exon 7 of 28	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5100 AN: 150456 Hom.: 105 Cov.: 31

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00157

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0439

GnomAD2 exomes AF: 0.0305 AC: 7640 AN: 250478 AF XY: 0.0310

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.0312

Gnomad EAS exome AF: 0.00142

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0388

GnomAD4 exome AF: 0.0354 AC: 51649 AN: 1460578 Hom.: 1101 Cov.: 34 AF XY: 0.0349 AC XY: 25375 AN XY: 726592

African (AFR) AF: 0.0299 AC: 1001 AN: 33452

American (AMR) AF: 0.0279 AC: 1245 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 796 AN: 26108

East Asian (EAS) AF: 0.00807 AC: 320 AN: 39666

South Asian (SAS) AF: 0.0113 AC: 970 AN: 86216

European-Finnish (FIN) AF: 0.0355 AC: 1891 AN: 53314

Middle Eastern (MID) AF: 0.0664 AC: 365 AN: 5498

European-Non Finnish (NFE) AF: 0.0386 AC: 42847 AN: 1111346

Other (OTH) AF: 0.0367 AC: 2214 AN: 60298

GnomAD4 genome AF: 0.0339 AC: 5104 AN: 150498 Hom.: 105 Cov.: 31 AF XY: 0.0346 AC XY: 2542 AN XY: 73384

African (AFR) AF: 0.0285 AC: 1166 AN: 40946

American (AMR) AF: 0.0409 AC: 617 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 89 AN: 3464

East Asian (EAS) AF: 0.00157 AC: 8 AN: 5094

South Asian (SAS) AF: 0.0103 AC: 49 AN: 4750

European-Finnish (FIN) AF: 0.0367 AC: 370 AN: 10086

Middle Eastern (MID) AF: 0.102 AC: 29 AN: 284

European-Non Finnish (NFE) AF: 0.0394 AC: 2669 AN: 67798

Other (OTH) AF: 0.0436 AC: 90 AN: 2064

Alfa AF: 0.0381 Hom.: 208

Bravo AF: 0.0335

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0465

EpiControl AF: 0.0475

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.20
DANN	Benign	0.45
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs16972658; hg19: chr16-21698949; COSMIC: COSV53751991;