dbSNP rs147865867: OTOF:p.Asp848Asn (chr2-26477025-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_194248.3(OTOF):c.2542G>A(p.Asp848Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,433,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84

Publications

1 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

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOF	NM_194248.3	MANE Select	c.2542G>A	p.Asp848Asn	missense	Exon 22 of 47	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3	MANE Plus Clinical	c.301G>A	p.Asp101Asn	missense	Exon 5 of 29	NP_919304.1	Q9HC10-2
OTOF	NM_001287489.2		c.2542G>A	p.Asp848Asn	missense	Exon 22 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2542G>A	p.Asp848Asn	missense	Exon 22 of 47	ENSP00000272371.2	Q9HC10-1
OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.301G>A	p.Asp101Asn	missense	Exon 5 of 29	ENSP00000344521.3	Q9HC10-2
OTOF	ENST00000402415.8	TSL:1	c.301G>A	p.Asp101Asn	missense	Exon 4 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes

AF:

0.000129

AC:

AN:

147396

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000472

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000448

AC:

AN:

223226

AF XY:

0.0000330

show subpopulations

Gnomad AFR exome

AF:

0.000714

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1285788

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

643578

show subpopulations

African (AFR)

AF:

0.000267

AC:

AN:

29960

American (AMR)

AF:

0.00

AC:

AN:

41710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23920

East Asian (EAS)

AF:

0.0000555

AC:

AN:

36026

South Asian (SAS)

AF:

0.00

AC:

AN:

81514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5280

European-Non Finnish (NFE)

AF:

0.00000413

AC:

AN:

968000

Other (OTH)

AF:

0.0000747

AC:

AN:

53568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

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:

0.000115

AC:

AN:

147528

Hom.:

Cov.:

AF XY:

0.0000973

AC XY:

AN XY:

71934

show subpopulations

African (AFR)

AF:

0.000421

AC:

AN:

40410

American (AMR)

AF:

0.00

AC:

AN:

14948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

4776

South Asian (SAS)

AF:

0.00

AC:

AN:

4516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66710

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.0000446

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000688

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000666

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.3

PhyloP100

7.8

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.80

MVP

0.92

MPC

0.56

ClinPred

0.88

GERP RS

4.9

Varity_R

0.86

gMVP

0.86

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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