dbSNP rs80356592: OTOF:p.Arg794His (chr2-26477441-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_194248.3(OTOF):c.2381G>A(p.Arg794His) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,596,440 control chromosomes in the GnomAD database, including 8 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 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 8 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5O:1

Conservation

PhyloP100: 5.89

Publications

14 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014693469).

BP6

Variant 2-26477441-C-T is Benign according to our data. Variant chr2-26477441-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21835.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00127 (193/152174) while in subpopulation NFE AF = 0.00209 (142/67992). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOF	NM_194248.3	MANE Select	c.2381G>A	p.Arg794His	missense	Exon 20 of 47	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3	MANE Plus Clinical	c.140G>A	p.Arg47His	missense	Exon 3 of 29	NP_919304.1	Q9HC10-2
OTOF	NM_001287489.2		c.2381G>A	p.Arg794His	missense	Exon 20 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.2381G>A	p.Arg794His	missense	Exon 20 of 47	ENSP00000272371.2	Q9HC10-1
OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.140G>A	p.Arg47His	missense	Exon 3 of 29	ENSP00000344521.3	Q9HC10-2
OTOF	ENST00000402415.8	TSL:1	c.140G>A	p.Arg47His	missense	Exon 2 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.00209

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00109

AC:

241

AN:

220574

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.000521

Gnomad AMR exome

AF:

0.000788

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00204

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00208

AC:

2999

AN:

1444266

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

1420

AN XY:

716558

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33254

American (AMR)

AF:

0.000920

AC:

AN:

42412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25748

East Asian (EAS)

AF:

0.00

AC:

AN:

39060

South Asian (SAS)

AF:

0.0000240

AC:

AN:

83216

European-Finnish (FIN)

AF:

0.0000982

AC:

AN:

50896

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00257

AC:

2834

AN:

1104204

Other (OTH)

AF:

0.00186

AC:

111

AN:

59742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

161

322

483

644

805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.00127

AC:

193

AN:

152174

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

41526

American (AMR)

AF:

0.00157

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00209

AC:

142

AN:

67992

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.00172

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000922

AC:

ESP6500EA

AF:

0.00210

AC:

ExAC

AF:

0.000907

AC:

109

Asia WGS

AF:

0.000289

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 (4)

Autosomal recessive nonsyndromic hearing loss 9 (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.8

PhyloP100

5.9

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.88

Sift

Uncertain

0.024

Sift4G

Uncertain

0.019

Polyphen

0.94

Vest4

0.88

MVP

0.93

MPC

0.57

ClinPred

0.054

GERP RS

4.7

Varity_R

0.45

gMVP

0.63

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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