rs215901

Variant names:

• chr16-21719128-C-T
• rs215901
• NM_144672.4:c.1630-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144672.4(OTOA):​c.1630-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,611,852 control chromosomes in the GnomAD database, including 347,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30277 hom., cov: 32)
  • Exomes 𝑓: 0.66 (317426 hom.)
• Consequence: OTOA NM_144672.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009088
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.457
• Publications: 19 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 (BayesDel_noAF=-0.69).
• BP6: Variant 16-21719128-C-T is Benign according to our data. Variant chr16-21719128-C-T is described in ClinVar as Benign. ClinVar VariationId is 47952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 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.1630-5C>T		splice_region intron	N/A	NP_653273.3
	OTOA	NM_001161683.2		c.1393-5C>T		splice_region intron	N/A	NP_001155155.1	Q7RTW8-4
	OTOA	NM_170664.3		c.658-5C>T		splice_region intron	N/A	NP_733764.1	Q7RTW8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	ENST00000646100.2	MANE Select	c.1630-5C>T		splice_region intron	N/A	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.1630-5C>T		splice_region intron	N/A	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.1672-5C>T		splice_region intron	N/A	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95438 AN: 151912 Hom.: 30259 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.625 AC: 156782 AN: 250836 AF XY: 0.636

Gnomad AFR exome AF: 0.583

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.656

Gnomad EAS exome AF: 0.504

Gnomad FIN exome AF: 0.637

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.644

GnomAD4 exome AF: 0.657 AC: 959542 AN: 1459822 Hom.: 317426 Cov.: 45 AF XY: 0.659 AC XY: 478791 AN XY: 726286

African (AFR) AF: 0.582 AC: 19451 AN: 33434

American (AMR) AF: 0.498 AC: 22292 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 16961 AN: 26124

East Asian (EAS) AF: 0.525 AC: 20833 AN: 39694

South Asian (SAS) AF: 0.668 AC: 57575 AN: 86186

European-Finnish (FIN) AF: 0.642 AC: 34262 AN: 53406

Middle Eastern (MID) AF: 0.718 AC: 3911 AN: 5450

European-Non Finnish (NFE) AF: 0.671 AC: 745433 AN: 1110500

Other (OTH) AF: 0.644 AC: 38824 AN: 60306

GnomAD4 genome AF: 0.628 AC: 95490 AN: 152030 Hom.: 30277 Cov.: 32 AF XY: 0.625 AC XY: 46485 AN XY: 74338

African (AFR) AF: 0.580 AC: 24045 AN: 41466

American (AMR) AF: 0.566 AC: 8642 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2236 AN: 3468

East Asian (EAS) AF: 0.509 AC: 2634 AN: 5172

South Asian (SAS) AF: 0.668 AC: 3226 AN: 4826

European-Finnish (FIN) AF: 0.636 AC: 6717 AN: 10564

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45862 AN: 67952

Other (OTH) AF: 0.636 AC: 1344 AN: 2114

Alfa AF: 0.659 Hom.: 70419

Bravo AF: 0.621

Asia WGS AF: 0.577 AC: 2010 AN: 3478

EpiCase AF: 0.676

EpiControl AF: 0.682

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		0.46
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000091
dbscSNV1_RF	Benign	0.0020
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: rs215901; hg19: chr16-21730449; COSMIC: COSV53751279;