rs111033351

Positions:

chr2-26480205-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP3BP4_Moderate

The NM_194248.3(OTOF):c.1910T>C(p.Ile637Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,590,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense, splice_region

Scores

Splicing: ADA: 0.2596

Clinical Significance

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

Conservation

PhyloP100: 9.32

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;

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.2363073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.1910T>C	p.Ile637Thr	missense_variant, splice_region_variant	16/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2 linkuse as main transcript	c.1910T>C	p.Ile637Thr	missense_variant, splice_region_variant	16/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.1910T>C	p.Ile637Thr	missense_variant, splice_region_variant	16/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000403946.7 linkuse as main transcript	c.1910T>C	p.Ile637Thr	missense_variant, splice_region_variant	16/46	5		ENSP00000385255	P4	Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000188

AC:

AN:

250500

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00247

Gnomad AMR exome

AF:

0.000145

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000549

AC:

AN:

1438082

Hom.:

Cov.:

AF XY:

0.0000502

AC XY:

AN XY:

716810

show subpopulations

Gnomad4 AFR exome

AF:

0.00166

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152326

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.000457

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:

0.000238

Hom.:

Bravo

AF:

0.000725

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2017

The p.Ile637Thr variant in OTOF has been previously identified by our laboratory in 4 individuals hearing loss, 3 of whom also have the p.Asp1406Asn variant of uncertain significance, suggesting that these two variants may occur in cis (on the same allele). One of those individuals was reported to have auditory neuropa thy/dys-synchrony and carried additional OTOF variants that were likely causativ e for the hearing loss. This variant has been identified in 0.2% (24/10294) of A frican chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs111033351). Computational prediction tools and conservatio n analysis suggest that this variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, the clinic al significance of the p.Ile637Thr variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.94

MVP

0.97

MPC

0.73

ClinPred

0.17

GERP RS

4.4

Varity_R

0.84

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.26

dbscSNV1_RF

Benign

0.67

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