Variant chr2-26460203-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_194248.3(OTOF):c.5816G>C(p.Arg1939Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,342 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1939Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.63

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-26460203-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.5816G>C	p.Arg1939Pro	missense_variant, splice_region_variant	46/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.3512+444G>C		intron_variant		ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.5816G>C	p.Arg1939Pro	missense_variant, splice_region_variant	46/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.3512+444G>C		intron_variant		1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000437

AC:

AN:

228634

Hom.:

AF XY:

0.00000814

AC XY:

AN XY:

122922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000358

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1448342

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;.;D;.

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.71

D;D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.6

.;.;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.25

PROVEAN

Pathogenic

-6.7

D;.;D;.

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0050

D;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;.

Polyphen

1.0

D;.;D;D

Vest4

0.65

MutPred

0.55

.;.;Gain of catalytic residue at R1939 (P = 0.0047);.;

MVP

0.91

MPC

0.77

ClinPred

0.99

GERP RS

2.3

Varity_R

0.97

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over