2-26527905-C-T

Position:

chr2-26527905-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_194248.3(OTOF):c.154G>A(p.Val52Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,870 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V52V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.154G>A	p.Val52Met	missense_variant	3/47	ENST00000272371.7
OTOF	NM_001287489.2 linkuse as main transcript	c.154G>A	p.Val52Met	missense_variant	3/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.154G>A	p.Val52Met	missense_variant	3/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000403946.7 linkuse as main transcript	c.154G>A	p.Val52Met	missense_variant	3/46	5		P4	Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000278

AC:

AN:

251410

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000235

AC:

344

AN:

1461580

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000252

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000256

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:2

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 23, 2015	Tne heterozygous variant was identified in the OTOF gene (c.154G>A; p.Val52Met) is considered a variant of uncertain significance. This variant has not been previously published in the literature and it is seen in 22 individuals in the ExAC database. Pathogenic mutations in this gene have been associated with autosomal recessive Deafness (MIM: 601071). The call for unknown significance for this variant is due to it's being a rare variant in an amino acid position that is conserved through birds. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 13, 2017

The p.Val52Met variant in OTOF has been previously reported by our laboratory in 1 individual with hearing loss, but a variant affecting the other copy of the g ene was not identified. This variant has also been reported in ClinVar (Variatio n ID# 164881) as of uncertain significance. The p.Val52Met variant has been iden tified in 28/34420 Latino chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs199992845); however its frequency is not high enough to rule out a pathogenic role. Computational prediction tools a nd conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val52Met variant is uncertain. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.55

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.29

Sift

Benign

0.21

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.91

P;.

Vest4

0.59

MVP

0.86

MPC

0.63

ClinPred

0.12

GERP RS

4.5

Varity_R

0.10

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over