dbSNP rs397517933: OTOF:p.Val34Leu (chr2-26537754-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_194248.3(OTOF):c.100G>C(p.Val34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.736

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29527146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.100G>C	p.Val34Leu	missense_variant	Exon 2 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.100G>C	p.Val34Leu	missense_variant	Exon 2 of 46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.100G>C	p.Val34Leu	missense_variant	Exon 2 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.100G>C	p.Val34Leu	missense_variant	Exon 2 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000617

AC:

AN:

162192

Hom.:

AF XY:

0.0000117

AC XY:

AN XY:

85470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000392

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402598

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000274

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.75

N;N

REVEL

Benign

0.15

Sift

Benign

0.25

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.0020

B;.

Vest4

0.50

MutPred

0.33

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.79

MPC

0.19

ClinPred

0.21

GERP RS

3.9

Varity_R

0.12

gMVP

0.49

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over