dbSNP rs143141993: OTOF:c.-107T>C (chr2-26477829-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_194322.3(OTOF):c.65T>C(p.Leu22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,581,032 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 13 hom. )

Consequence

OTOF
NM_194322.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.777

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

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074367225).

BP6

Variant 2-26477829-A-G is Benign according to our data. Variant chr2-26477829-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48189.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00263 (401/152262) while in subpopulation AMR AF = 0.00431 (66/15300). AF 95% confidence interval is 0.00367. There are 2 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR 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.2215-80T>C		intron	N/A	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3	MANE Plus Clinical	c.-28+15T>C		intron	N/A	NP_919304.1	Q9HC10-2
OTOF	NM_194322.3		c.65T>C	p.Leu22Pro	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.-107T>C	5_prime_UTR	Exon 1 of 29	ENSP00000383906.4	A0A2U3TZT7
OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2215-80T>C	intron	N/A	ENSP00000272371.2	Q9HC10-1
OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.-28+15T>C	intron	N/A	ENSP00000344521.3	Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

401

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00267

AC:

519

AN:

194268

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.000955

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.00145

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000158

Gnomad NFE exome

AF:

0.00456

Gnomad OTH exome

AF:

0.00333

GnomAD4 exome

AF:

0.00397

AC:

5675

AN:

1428770

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

2728

AN XY:

707892

show subpopulations

African (AFR)

AF:

0.000614

AC:

AN:

32586

American (AMR)

AF:

0.00392

AC:

155

AN:

39500

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

25536

East Asian (EAS)

AF:

0.00

AC:

AN:

37706

South Asian (SAS)

AF:

0.000133

AC:

AN:

82696

European-Finnish (FIN)

AF:

0.000179

AC:

AN:

50246

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00477

AC:

5226

AN:

1095544

Other (OTH)

AF:

0.00361

AC:

214

AN:

59224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

304

609

913

1218

1522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<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:

0.00263

AC:

401

AN:

152262

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41572

American (AMR)

AF:

0.00431

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00406

AC:

276

AN:

68000

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00400

Hom.:

Bravo

AF:

0.00347

ExAC

AF:

0.00212

AC:

251

Asia WGS

AF:

0.000577

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)

not specified (2)

OTOF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.66

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.26

M_CAP

Benign

0.043

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.95

PhyloP100

-0.78

Polyphen

0.020

ClinPred

0.037

GERP RS

2.3

PromoterAI

0.060

Neutral

(source)

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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