dbSNP rs111033393: OTOF:p.Thr1688Met (chr2-26464004-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS1

The NM_194248.3(OTOF):c.5063C>T(p.Thr1688Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1688T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 8.10

Publications

10 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
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 -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.054777652).

BP6

Variant 2-26464004-G-A is Benign according to our data. Variant chr2-26464004-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48248.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00133 (203/152290) while in subpopulation NFE AF = 0.0021 (143/68032). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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
OTOF	NM_194248.3	MANE Select	c.5063C>T	p.Thr1688Met	missense	Exon 40 of 47	NP_919224.1
OTOF	NM_194323.3	MANE Plus Clinical	c.2762C>T	p.Thr921Met	missense	Exon 23 of 29	NP_919304.1
OTOF	NM_001287489.2		c.5063C>T	p.Thr1688Met	missense	Exon 40 of 46	NP_001274418.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOF	ENST00000272371.7	TSL:1 MANE Select	c.5063C>T	p.Thr1688Met	missense	Exon 40 of 47	ENSP00000272371.2
OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2762C>T	p.Thr921Met	missense	Exon 23 of 29	ENSP00000344521.3
OTOF	ENST00000402415.8	TSL:1	c.2822C>T	p.Thr941Met	missense	Exon 22 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00126

AC:

315

AN:

250620

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.000556

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00168

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00143

AC:

2095

AN:

1461474

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1004

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.00183

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000358

AC:

AN:

53014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00166

AC:

1845

AN:

1112004

Other (OTH)

AF:

0.00123

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

128

256

384

512

640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

140

210

280

350

<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:

0.00133

AC:

203

AN:

152290

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41566

American (AMR)

AF:

0.00209

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00210

AC:

143

AN:

68032

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00185

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00178

ClinVar

ClinVar submissions as Germline

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 (2)

not specified (2)

OTOF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.055

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.0

PhyloP100

8.1

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.83

MVP

0.94

MPC

0.60

ClinPred

0.034

GERP RS

4.4

Varity_R

0.53

gMVP

0.80

Mutation Taster

=30/70

disease causing

(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

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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