rs117985483

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_194248.3(OTOF):c.237G>A(p.Gly79Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,597,790 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene OTOF is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 4 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.477

Publications

0 publications found

Variant links:

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

OTOF links:

Genome browser will be placed here

ACMG classification

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

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 2-26519100-C-T is Benign according to our data. Variant chr2-26519100-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48195.

BP7

Synonymous conserved (PhyloP=0.477 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000624 (95/152322) while in subpopulation EAS AF = 0.00753 (39/5180). AF 95% confidence interval is 0.00566. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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.237G>A	p.Gly79Gly	synonymous	Exon 4 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.237G>A	p.Gly79Gly	synonymous	Exon 4 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.237G>A	p.Gly79Gly	synonymous	Exon 4 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.237G>A	p.Gly79Gly	synonymous	Exon 4 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00751

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000938

AC:

214

AN:

228040

AF XY:

0.000951

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000213

Gnomad EAS exome

AF:

0.00415

Gnomad FIN exome

AF:

0.00523

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.000351

GnomAD4 exome

AF:

0.000460

AC:

665

AN:

1445468

Hom.:

Cov.:

AF XY:

0.000461

AC XY:

331

AN XY:

717816

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33344

American (AMR)

AF:

0.00

AC:

AN:

43590

Ashkenazi Jewish (ASJ)

AF:

0.000546

AC:

AN:

25650

East Asian (EAS)

AF:

0.00415

AC:

164

AN:

39532

South Asian (SAS)

AF:

0.000972

AC:

AN:

84350

European-Finnish (FIN)

AF:

0.00532

AC:

278

AN:

52276

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000817

AC:

AN:

1101288

Other (OTH)

AF:

0.000553

AC:

AN:

59694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000624

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00753

AC:

AN:

5180

South Asian (SAS)

AF:

0.00207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000400

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 9 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.5

(source)

DANN

Benign

0.62

PhyloP100

0.48

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over