rs80356573

Variant names:

• chr2-26474612-C-T
• rs80356573
• NM_194248.3:c.3189G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26474612-C-T
• chr2-26474612-C-G

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.3189G>A​(p.Ala1063Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,148 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 31)
  • Exomes 𝑓: 0.020 (355 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: -3.09
• Publications: 5 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: AR, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-26474612-C-T is Benign according to our data. Variant chr2-26474612-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21843.
• BP7: Synonymous conserved (PhyloP=-3.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2279/152272) while in subpopulation NFE AF = 0.0195 (1327/68018). AF 95% confidence interval is 0.0186. There are 19 homozygotes in GnomAd4. There are 1029 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR 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.3189G>A	p.Ala1063Ala	synonymous	Exon 26 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.948G>A	p.Ala316Ala	synonymous	Exon 9 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.3189G>A	p.Ala1063Ala	synonymous	Exon 26 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.3189G>A	p.Ala1063Ala	synonymous	Exon 26 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.948G>A	p.Ala316Ala	synonymous	Exon 9 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.948G>A	p.Ala316Ala	synonymous	Exon 8 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2276 AN: 152154 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0145 AC: 3639 AN: 250580 AF XY: 0.0148

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0195 AC: 28520 AN: 1460876 Hom.: 355 Cov.: 33 AF XY: 0.0190 AC XY: 13795 AN XY: 726752

African (AFR) AF: 0.0102 AC: 340 AN: 33472

American (AMR) AF: 0.00789 AC: 353 AN: 44716

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00325 AC: 280 AN: 86256

European-Finnish (FIN) AF: 0.0227 AC: 1195 AN: 52564

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.0223 AC: 24813 AN: 1111882

Other (OTH) AF: 0.0167 AC: 1009 AN: 60386

GnomAD4 genome AF: 0.0150 AC: 2279 AN: 152272 Hom.: 19 Cov.: 31 AF XY: 0.0138 AC XY: 1029 AN XY: 74438

African (AFR) AF: 0.0104 AC: 433 AN: 41554

American (AMR) AF: 0.0123 AC: 188 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0195 AC: 1327 AN: 68018

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0164 Hom.: 10

Bravo AF: 0.0147

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0222

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)
-	1	-	Autosomal recessive nonsyndromic hearing loss 9 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.6
DANN	Benign	0.73
PhyloP100		-3.1
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs80356573; hg19: chr2-26697480; COSMIC: COSV55496428; COSMIC: COSV55496428;