rs181092713

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001393500.2(TOMT):c.253G>A(p.Val85Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,491,510 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

TOMT
NM_001393500.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.06

Publications

2 publications found

Variant links:

Genes affected

TOMT (HGNC:55527): (transmembrane O-methyltransferase) This gene encodes a catechol-O-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to a hydroxyl group of catechols and is essential for auditory and vestibular function. Mutations in this gene have been associated with nonsyndromic deafness. Readthrough transcription is observed across this gene and the adjacent leucine-rich repeat containing 51 gene. A third locus (GeneID:220074) is defined to represent the readthrough transcripts. [provided by RefSeq, Feb 2021]

TOMT links:

LRTOMT (HGNC:25033): (leucine rich transmembrane and O-methyltransferase domain containing) This locus represents naturally occurring readthrough transcription between the neighboring LRRC51 (leucine-rich repeat containing 51) and TOMT (transmembrane O-methyltransferase) genes on chromosome 11. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. Multiple reports implicate mutations in this gene in nonsyndromic deafness.[provided by RefSeq, Feb 2021]

LRTOMT links:

ANAPC15 (HGNC:24531): (anaphase promoting complex subunit 15) Involved in regulation of mitotic cell cycle spindle assembly checkpoint. Part of anaphase-promoting complex. [provided by Alliance of Genome Resources, Apr 2022]

ANAPC15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001393500.2

BP4

Computational evidence support a benign effect (MetaRNN=0.0081934035).

BP6

Variant 11-72106204-G-A is Benign according to our data. Variant chr11-72106204-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44039.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00375 (571/152342) while in subpopulation AFR AF = 0.0133 (552/41574). AF 95% confidence interval is 0.0124. There are 4 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMT	NM_001393500.2 link	c.253G>A	p.Val85Ile	missense_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3 link	c.253G>A	p.Val85Ile	missense_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1		A0A2R8Y5M8
LRTOMT	ENST00000307198.11 link	c.352G>A	p.Val118Ile	missense_variant	Exon 5 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes

AF:

0.00374

AC:

570

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00104

AC:

124

AN:

118756

AF XY:

0.000785

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.000423

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000212

Gnomad OTH exome

AF:

0.000285

GnomAD4 exome

AF:

0.000378

AC:

506

AN:

1339168

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

221

AN XY:

653256

show subpopulations

African (AFR)

AF:

0.0147

AC:

450

AN:

30648

American (AMR)

AF:

0.000430

AC:

AN:

32582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22684

East Asian (EAS)

AF:

0.00

AC:

AN:

34948

South Asian (SAS)

AF:

0.00

AC:

AN:

74138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35248

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5480

European-Non Finnish (NFE)

AF:

0.00000286

AC:

AN:

1047744

Other (OTH)

AF:

0.000682

AC:

AN:

55696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00375

AC:

571

AN:

152342

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0133

AC:

552

AN:

41574

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00560

Hom.:

Bravo

AF:

0.00422

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00140

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 63

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Mar 13, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val118Ile in Exon 05 of LRTOMT: This variant is not expected to have clinical si gnificance because it has been identified in 1.5% (21/1384) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.68

T;.;T

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

L;L;.

PhyloP100

1.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.74

N;N;.

REVEL

Benign

0.028

Sift

Benign

0.24

T;T;.

Sift4G

Benign

0.23

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.094

MVP

0.11

MPC

0.054

ClinPred

0.017

GERP RS

1.4

PromoterAI

0.025

Neutral

(source)

Varity_R

0.12

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

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

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rs181092713

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over