rs139201321

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_194248.3(OTOF):c.4951G>A(p.Asp1651Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,602,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D1651D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.87

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;

BP6

Variant 2-26464878-C-T is Benign according to our data. Variant chr2-26464878-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164839.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.4951G>A	p.Asp1651Asn	missense_variant	39/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.2650G>A	p.Asp884Asn	missense_variant	22/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.4951G>A	p.Asp1651Asn	missense_variant	39/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.2650G>A	p.Asp884Asn	missense_variant	22/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

244374

Hom.:

AF XY:

0.00000757

AC XY:

AN XY:

132144

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.00

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:

0.00000965

AC:

AN:

1450760

Hom.:

Cov.:

AF XY:

0.00000693

AC XY:

AN XY:

721038

show subpopulations

Gnomad4 AFR exome

AF:

0.000396

Gnomad4 AMR exome

AF:

0.00

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:

0.0000167

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2013

The Asp1651Asn variant in OTOF has not been previously reported in individuals w ith hearing loss but was detected in 0.02% (1/4406) of African American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP r s139201321). Computational tools (amino acid biochemical properties, conservati on, AlignGVGD, SIFT, PolyPhen-2) do not provide strong evidence for or against a n impact to the protein. Additional information is required to establish the cl inical significance of this variant. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.4951G>A (p.D1651N) alteration is located in exon 39 (coding exon 39) of the OTOF gene. This alteration results from a G to A substitution at nucleotide position 4951, causing the aspartic acid (D) at amino acid position 1651 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.29

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.52

D;D;D;D;D;D

MetaSVM

Benign

-0.76

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.0

D;D;.;D;D;.

REVEL

Benign

0.14

Sift

Uncertain

0.028

D;D;.;D;D;.

Sift4G

Benign

0.11

T;T;.;T;T;.

Polyphen

0.73

P;B;.;D;.;D

Vest4

0.85

MVP

0.82

MPC

0.64

ClinPred

0.90

GERP RS

4.9

Varity_R

0.25

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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