Genetic Variant OTOF:p.Arg1157Gln (chr2-26473506-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.3470G>A(p.Arg1157Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,612,842 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1157W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0085 ( 7 hom., cov: 33)

Exomes 𝑓: 0.013 ( 139 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 2.76

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, 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=0.0115759075).

BP6

Variant 2-26473506-C-T is Benign according to our data. Variant chr2-26473506-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21845.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00847 (1290/152238) while in subpopulation NFE AF = 0.0146 (990/68002). AF 95% confidence interval is 0.0138. There are 7 homozygotes in GnomAd4. There are 538 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOF	NM_194248.3	MANE Select	c.3470G>A	p.Arg1157Gln	missense	Exon 28 of 47	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3	MANE Plus Clinical	c.1229G>A	p.Arg410Gln	missense	Exon 11 of 29	NP_919304.1	Q9HC10-2
OTOF	NM_001287489.2		c.3470G>A	p.Arg1157Gln	missense	Exon 28 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.3470G>A	p.Arg1157Gln	missense	Exon 28 of 47	ENSP00000272371.2	Q9HC10-1
OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.1229G>A	p.Arg410Gln	missense	Exon 11 of 29	ENSP00000344521.3	Q9HC10-2
OTOF	ENST00000402415.8	TSL:1	c.1229G>A	p.Arg410Gln	missense	Exon 10 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes

AF:

0.00849

AC:

1291

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00809

AC:

2022

AN:

250062

AF XY:

0.00793

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.00955

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00146

Gnomad NFE exome

AF:

0.0132

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0129

AC:

18796

AN:

1460604

Hom.:

139

Cov.:

AF XY:

0.0124

AC XY:

9043

AN XY:

726668

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33480

American (AMR)

AF:

0.0101

AC:

451

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000870

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

52280

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0156

AC:

17295

AN:

1111922

Other (OTH)

AF:

0.0116

AC:

701

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1015

2030

3045

4060

5075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.00847

AC:

1290

AN:

152238

Hom.:

Cov.:

AF XY:

0.00723

AC XY:

538

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41536

American (AMR)

AF:

0.00974

AC:

149

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

990

AN:

68002

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0110

Hom.:

Bravo

AF:

0.00954

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0150

AC:

129

ExAC

AF:

0.00798

AC:

969

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0149

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Autosomal recessive nonsyndromic hearing loss 9 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

Eigen

Benign

-0.053

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.29

MutationAssessor

Benign

-0.99

PhyloP100

2.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.36

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.30

Vest4

0.37

MVP

0.88

MPC

0.71

ClinPred

0.013

GERP RS

5.2

PromoterAI

0.042

Neutral

(source)

Varity_R

0.25

gMVP

0.69

Mutation Taster

=96/4

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

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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