chr11-72107961-G-A

Position:

• chr11-72107961-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001393500.2(TOMT):​c.298G>A​(p.Ala100Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,416 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A100P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

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]

LRTOMT (HGNC:):

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]

ACMG classification

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=0.046556443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMT	NM_001393500.2	c.298G>A	p.Ala100Thr	missense_variant	2/3	ENST00000541899.3
LRTOMT	NM_001145309.4	c.397G>A	p.Ala133Thr	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMT	ENST00000541899.3	c.298G>A	p.Ala100Thr	missense_variant	2/3	5	NM_001393500.2	P1
ANAPC15	ENST00000502597.2	c.64-356C>T		intron_variant		1
ANAPC15	ENST00000543050.5	c.319-356C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000128 AC: 2 AN: 156626 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 82994

Gnomad AFR exome AF: 0.00

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: 0.0000330

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399416 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690218

Gnomad4 AFR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000759 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 133 of the LRTOMT protein (p.Ala133Thr). This variant is present in population databases (rs76657474, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with LRTOMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1496548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRTOMT protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.051	T;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.75	T;.;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.37	N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.14	N;N;.
REVEL	Benign	0.023
Sift	Benign	0.55	T;T;.
Sift4G	Benign	0.57	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.075
MutPred		0.37		Gain of glycosylation at A133 (P = 0.0423);Gain of glycosylation at A133 (P = 0.0423);.;
MVP		0.28
MPC		0.062
ClinPred		0.041	T
GERP RS		2.9
Varity_R		0.082
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs76657474; hg19: chr11-71819007;