rs149236286

Variant names:

• chr2-26467129-G-A
• rs149236286
• NM_194248.3:c.4332C>T
• OTOF p.Thr1444Thr

Your query was ambiguous. Multiple possible variants found:

• chr2-26467129-G-A
• chr2-26467129-G-C
• chr2-26467129-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_194248.3(OTOF):​c.4332C>T​(p.Thr1444Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,904 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1444T) has been classified as Likely benign. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.015 (18 hom., cov: 32)
  • Exomes 𝑓: 0.019 (353 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -4.61
• Publications: 3 publications found

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-26467129-G-A is Benign according to our data. Variant chr2-26467129-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48233.
• BP7: Synonymous conserved (PhyloP=-4.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2221/152206) while in subpopulation NFE AF = 0.0195 (1329/68010). AF 95% confidence interval is 0.0187. There are 18 homozygotes in GnomAd4. There are 1014 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. 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
	OTOF	NM_194248.3	MANE Select	c.4332C>T	p.Thr1444Thr	synonymous	Exon 35 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2031C>T	p.Thr677Thr	synonymous	Exon 18 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.4332C>T	p.Thr1444Thr	synonymous	Exon 35 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.4332C>T	p.Thr1444Thr	synonymous	Exon 35 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2031C>T	p.Thr677Thr	synonymous	Exon 18 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.2091C>T	p.Thr697Thr	synonymous	Exon 17 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2219 AN: 152088 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0144 AC: 3622 AN: 251204 AF XY: 0.0146

Gnomad AFR exome AF: 0.00911

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0195 AC: 28459 AN: 1461698 Hom.: 353 Cov.: 35 AF XY: 0.0189 AC XY: 13757 AN XY: 727170

African (AFR) AF: 0.00830 AC: 278 AN: 33480

American (AMR) AF: 0.00794 AC: 355 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 467 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00322 AC: 278 AN: 86254

European-Finnish (FIN) AF: 0.0227 AC: 1207 AN: 53268

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.0223 AC: 24800 AN: 1111978

Other (OTH) AF: 0.0168 AC: 1012 AN: 60390

GnomAD4 genome AF: 0.0146 AC: 2221 AN: 152206 Hom.: 18 Cov.: 32 AF XY: 0.0136 AC XY: 1014 AN XY: 74398

African (AFR) AF: 0.00891 AC: 370 AN: 41528

American (AMR) AF: 0.0125 AC: 191 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0195 AC: 1329 AN: 68010

Other (OTH) AF: 0.0119 AC: 25 AN: 2108

Alfa AF: 0.0146 Hom.: 9

Bravo AF: 0.0141

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0212

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.0030
DANN	Benign	0.69
PhyloP100		-4.6
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149236286;

hg19: chr2-26689997;

COSMIC: COSV55515962;

COSMIC: COSV55515962;