11-72108067-C-G

Position:

• chr11-72108067-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001393500.2(TOMT):​c.404C>G​(p.Thr135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,406 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. T135M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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 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=0.14711043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMT	NM_001393500.2	c.404C>G	p.Thr135Arg	missense_variant	2/3	ENST00000541899.3
LRTOMT	NM_001145309.4	c.503C>G	p.Thr168Arg	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMT	ENST00000541899.3	c.404C>G	p.Thr135Arg	missense_variant	2/3	5	NM_001393500.2	P1
ANAPC15	ENST00000502597.2	c.64-462G>C		intron_variant		1
ANAPC15	ENST00000543050.5	c.319-462G>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390406 Hom.: 0 Cov.: 31 AF XY: 0.00000292 AC XY: 2 AN XY: 684560

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: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 32

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

Apr 08, 2022

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 168 of the LRTOMT protein (p.Thr168Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LRTOMT-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	0.11
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.063	T;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.39	N;N;.
REVEL	Benign	0.26
Sift	Benign	0.20	T;T;.
Sift4G	Benign	0.32	T;T;.
Polyphen		0.21	B;B;.
Vest4		0.50
MutPred		0.51		Loss of phosphorylation at T168 (P = 0.0484);Loss of phosphorylation at T168 (P = 0.0484);.;
MVP		0.50
MPC		0.29
ClinPred		0.46	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-71819113;