rs540371915

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001393500.2(TOMT):c.596C>T(p.Ala199Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,550,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

TOMT
NM_001393500.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.19

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:):

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06716108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMT	NM_001393500.2 linkuse as main transcript	c.596C>T	p.Ala199Val	missense_variant	3/3	ENST00000541899.3
LRTOMT	NM_001145309.4 linkuse as main transcript	c.695C>T	p.Ala232Val	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TOMT	ENST00000541899.3 linkuse as main transcript	c.596C>T	p.Ala199Val	missense_variant	3/3	5	NM_001393500.2	P1
ANAPC15	ENST00000502597.2 linkuse as main transcript	c.64-1139G>A		intron_variant		1
ANAPC15	ENST00000543050.5 linkuse as main transcript	c.319-1139G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000337

AC:

AN:

154228

Hom.:

AF XY:

0.000342

AC XY:

AN XY:

81874

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000484

AC:

676

AN:

1398078

Hom.:

Cov.:

AF XY:

0.000481

AC XY:

332

AN XY:

689608

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.000560

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000328

Gnomad4 FIN exome

AF:

0.000104

Gnomad4 NFE exome

AF:

0.000548

Gnomad4 OTH exome

AF:

0.000500

GnomAD4 genome

AF:

0.000368

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000352

Hom.:

Bravo

AF:

0.000332

ExAC

AF:

0.000151

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 13, 2022	BS1_supporting -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 12, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Ala232Val var iant in LRTOMT has been previously identified by our laboratory in 2 Caucasian i ndividuals with hearing loss, but a second variant affecting the other copy of t he gene was not identified in either individual and pathogenic variants in a dif ferent gene explained the hearing loss in one of them. This variant has also bee n identified in 2/7684 South Asian chromosomes and in 2/8160 European chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs540371915). The alanine (Ala) at position 232 is not highly conserved in ma mmals and evolutionary distant species, and 1 mammal (Chinese tree shrew) carrie s a valine (Val), raising the possibility that this change at this position may be tolerated. Additional computational prediction tools do not provide strong su pport for or against an impact to the protein. In summary, while the clinical si gnificance of the p.Ala323Val variant is uncertain, these data suggest that it i s more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.32

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.24

T;T;.

Eigen

Benign

-0.066

Eigen_PC

Benign

0.094

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.72

T;.;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

2.0

M;M;.

MutationTaster

Benign

1.0

D;N;N;N;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

N;N;.

REVEL

Benign

0.16

Sift

Uncertain

0.0040

D;D;.

Sift4G

Uncertain

0.040

D;D;.

Polyphen

0.0010

B;B;.

Vest4

0.083

MVP

0.76

MPC

0.12

ClinPred

0.070

GERP RS

4.6

Varity_R

0.092

gMVP

0.46

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over