Variant 11-72108117-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001393500.2(TOMT):c.454A>G(p.Met152Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000222 in 1,350,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TOMT
NM_001393500.2 missense, splice_region

Scores

Splicing: ADA: 0.006108

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12430939).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMT	NM_001393500.2 linkuse as main transcript	c.454A>G	p.Met152Val	missense_variant, splice_region_variant	2/3	ENST00000541899.3
LRTOMT	NM_001145309.4 linkuse as main transcript	c.553A>G	p.Met185Val	missense_variant, splice_region_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TOMT	ENST00000541899.3 linkuse as main transcript	c.454A>G	p.Met152Val	missense_variant, splice_region_variant	2/3	5	NM_001393500.2	P1
ANAPC15	ENST00000502597.2 linkuse as main transcript	c.64-512T>C		intron_variant		1
ANAPC15	ENST00000543050.5 linkuse as main transcript	c.319-512T>C		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000222

AC:

AN:

1350240

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

660034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000568

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.51e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2022

The c.553A>G (p.M185V) alteration is located in exon 6 (coding exon 4) of the LRTOMT gene. This alteration results from a A to G substitution at nucleotide position 553, causing the methionine (M) at amino acid position 185 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.044

T;T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

T;.;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.34

N;N;.

MutationTaster

Benign

0.50

D;D;N;N;D;D

PrimateAI

Benign

0.23

PROVEAN

Benign

0.19

N;N;.

REVEL

Benign

0.19

Sift

Benign

0.56

T;T;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0010

B;B;.

Vest4

0.22

MutPred

0.57

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;

MVP

0.55

MPC

0.066

ClinPred

0.11

GERP RS

4.6

Varity_R

0.11

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0061

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 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