dbSNP rs76130130: OTOF:c.-104T>G (chr2-26477826-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_194322.3(OTOF):c.68T>G(p.Ile23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,587,232 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene OTOF is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 36 hom. )

Consequence

OTOF
NM_194322.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.168

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004008025).

BP6

Variant 2-26477826-A-C is Benign according to our data. Variant chr2-26477826-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00341 (519/152214) while in subpopulation NFE AF = 0.00487 (331/67992). AF 95% confidence interval is 0.00444. There are 1 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 36 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194322.3. 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.2215-77T>G		intron	N/A	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3	MANE Plus Clinical	c.-28+18T>G		intron	N/A	NP_919304.1	Q9HC10-2
OTOF	NM_194322.3		c.68T>G	p.Ile23Ser	missense	Exon 1 of 29	NP_919303.1	Q9HC10-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OTOF	ENST00000402415.8	TSL:1	c.-104T>G	5_prime_UTR	Exon 1 of 29	ENSP00000383906.4	A0A2U3TZT7
OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2215-77T>G	intron	N/A	ENSP00000272371.2	Q9HC10-1
OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.-28+18T>G	intron	N/A	ENSP00000344521.3	Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00341

AC:

519

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00487

Gnomad OTH

AF:

0.00817

GnomAD2 exomes

AF:

0.00430

AC:

866

AN:

201304

AF XY:

0.00414

show subpopulations

Gnomad AFR exome

AF:

0.000663

Gnomad AMR exome

AF:

0.00526

Gnomad ASJ exome

AF:

0.0137

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000207

Gnomad NFE exome

AF:

0.00604

Gnomad OTH exome

AF:

0.00708

GnomAD4 exome

AF:

0.00535

AC:

7682

AN:

1435018

Hom.:

Cov.:

AF XY:

0.00517

AC XY:

3677

AN XY:

711602

show subpopulations

African (AFR)

AF:

0.000854

AC:

AN:

32786

American (AMR)

AF:

0.00537

AC:

217

AN:

40436

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

401

AN:

25624

East Asian (EAS)

AF:

0.00

AC:

AN:

38092

South Asian (SAS)

AF:

0.000805

AC:

AN:

83252

European-Finnish (FIN)

AF:

0.000257

AC:

AN:

50642

Middle Eastern (MID)

AF:

0.00470

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00602

AC:

6621

AN:

1098964

Other (OTH)

AF:

0.00518

AC:

308

AN:

59480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

422

844

1266

1688

2110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.00341

AC:

519

AN:

152214

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41548

American (AMR)

AF:

0.00353

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00487

AC:

331

AN:

67992

Other (OTH)

AF:

0.00808

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

114

143

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:

0.00484

Hom.:

Bravo

AF:

0.00395

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00542

AC:

ExAC

AF:

0.00362

AC:

430

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

1.0

(source)

DANN

Benign

0.94

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.34

M_CAP

Benign

0.016

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.99

PhyloP100

-0.17

Polyphen

0.0010

ClinPred

0.060

GERP RS

-4.5

PromoterAI

0.0074

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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