2-26460203-C-T

Position:

chr2-26460203-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_194248.3(OTOF):c.5816G>A(p.Arg1939Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,600,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1939W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:1O:1

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-26460204-G-A is described in Lovd as [Pathogenic].

PP5

Variant 2-26460203-C-T is Pathogenic according to our data. Variant chr2-26460203-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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>A	p.Arg1939Gln	missense_variant, splice_region_variant	46/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.3512+444G>A		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>A	p.Arg1939Gln	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>A		intron_variant		1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000612

AC:

AN:

228634

Hom.:

AF XY:

0.0000488

AC XY:

AN XY:

122922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.000523

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:

0.0000193

AC:

AN:

1448342

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

719068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000116

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.000203

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000814

Gnomad4 OTH exome

AF:

0.0000835

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Pathogenic:1Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	Oct 21, 2014	Our laboratory reported three molecular diagnoses in OTOF (NM_004802.3, c.3515G>A), SLC12A6 (NM_001042494.1, c.73dup) and USH2A (NM_206933.2, c.13709G>A and c.5858C>G in trans), in one individual with reported features of congenital deafness, autism, delayed speech, macrocephaly, and skin anomalies that include hyperpigmented areas, excessively stretchy skin, poor wound healing, and keloids. Heterozygotes for this variant would be expected to be asymptomatic carriers. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 23, 2019	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1939 of the OTOF protein (p.Arg1939Gln). This variant is present in population databases (rs80356605, gnomAD 0.07%). This missense change has been observed in individual(s) with auditory neuropathy spectrum disorder and/or deafness (PMID: 23562982, 34536124). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese ancestry (PMID: 22575033, 34424407, 34536124). This variant is also known as c.3515G>A (p.Arg1172Gln). ClinVar contains an entry for this variant (Variation ID: 6136). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Arg1939 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been observed in individuals with OTOF-related conditions (PMID: 34536124), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 14, 2022	PP3, PM2_supporting -

Auditory neuropathy, autosomal recessive, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;.;D;.

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.77

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.6

.;.;H;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.8

D;.;D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;.

Polyphen

1.0

D;.;D;D

Vest4

0.38

MVP

0.91

MPC

0.64

ClinPred

0.97

GERP RS

2.3

Varity_R

0.88

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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