11-72106061-G-A

Position:

• chr11-72106061-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001393500.2(TOMT):​c.110G>A​(p.Arg37Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,550,752 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (1 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.65

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:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0838024).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152310) while in subpopulation EAS AF= 0.00193 (10/5180). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.110G>A	p.Arg37Gln	missense_variant	1/3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145309.4	c.209G>A	p.Arg70Gln	missense_variant	7/9		NP_001138781.1
LRTOMT	NM_001145308.5	c.209G>A	p.Arg70Gln	missense_variant	5/7		NP_001138780.1
LRTOMT	NM_001145310.4	c.89G>A	p.Arg30Gln	missense_variant	7/9		NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3	c.110G>A	p.Arg37Gln	missense_variant	1/3	5	NM_001393500.2	ENSP00000494667	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000129 AC: 20 AN: 154834 Hom.: 0 AF XY: 0.000109 AC XY: 9 AN XY: 82242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00156

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 45 AN: 1398442 Hom.: 1 Cov.: 31 AF XY: 0.0000319 AC XY: 22 AN XY: 689798

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000532

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000372

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74468

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.209G>A (p.R70Q) alteration is located in exon 5 (coding exon 3) of the LRTOMT gene. This alteration results from a G to A substitution at nucleotide position 209, causing the arginine (R) at amino acid position 70 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 63 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 05, 2021

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 70 of the LRTOMT protein (p.Arg70Gln). This variant is present in population databases (rs188715129, gnomAD 0.2%). 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: 305991). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 22, 2019

The p.Arg70Gln variant in LRTOMT is classified as likely benign because it has been identified in 0.19% (24/12456) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.97	N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.31	T;T;.
Polyphen		0.82	P;P;.
Vest4		0.096
MVP		0.89
MPC		0.072
ClinPred		0.18	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.41

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: rs188715129; hg19: chr11-71817107;