11-72108067-C-T

Variant names:

• chr11-72108067-C-T
• rs537610140
• NM_001393500.2:c.404C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001393500.2(TOMT):​c.404C>T​(p.Thr135Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,542,694 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T135A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (9 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.74
• Publications: 0 publications found

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:25033): (leucine rich transmembrane and O-methyltransferase domain containing) This locus represents naturally occurring readthrough transcription between the neighboring LRRC51 (leucine-rich repeat containing 51) and TOMT (transmembrane O-methyltransferase) genes on chromosome 11. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. Multiple reports implicate mutations in this gene in nonsyndromic deafness.[provided by RefSeq, Feb 2021]

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066455007).
• BP6: Variant 11-72108067-C-T is Benign according to our data. Variant chr11-72108067-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305994.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000387 (59/152294) while in subpopulation SAS AF = 0.0116 (56/4824). AF 95% confidence interval is 0.00918. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393500.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	NM_001393500.2	MANE Select	c.404C>T	p.Thr135Met	missense	Exon 2 of 3	NP_001380429.1	A0A2R8Y5M8
	LRTOMT	NM_001145308.5		c.503C>T	p.Thr168Met	missense	Exon 6 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.503C>T	p.Thr168Met	missense	Exon 8 of 9	NP_001138781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	ENST00000541899.3	TSL:5 MANE Select	c.404C>T	p.Thr135Met	missense	Exon 2 of 3	ENSP00000494667.1	A0A2R8Y5M8
	LRTOMT	ENST00000307198.11	TSL:2	c.503C>T	p.Thr168Met	missense	Exon 6 of 7	ENSP00000305742.7
	ANAPC15	ENST00000502597.2	TSL:1	c.64-462G>A		intron	N/A	ENSP00000441774.1	F5GWM6

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00139 AC: 211 AN: 151826 AF XY: 0.00196

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000343

Gnomad OTH exome AF: 0.000237

GnomAD4 exome AF: 0.000583 AC: 810 AN: 1390400 Hom.: 9 Cov.: 31 AF XY: 0.000809 AC XY: 554 AN XY: 684554

African (AFR) AF: 0.0000957 AC: 3 AN: 31342

American (AMR) AF: 0.0000575 AC: 2 AN: 34802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24686

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35580

South Asian (SAS) AF: 0.00938 AC: 738 AN: 78698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49146

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5654

European-Non Finnish (NFE) AF: 0.0000103 AC: 11 AN: 1072930

Other (OTH) AF: 0.000886 AC: 51 AN: 57562

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74462

African (AFR) AF: 0.0000481 AC: 2 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.00269 AC: 69

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 63 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	LRTOMT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N
PhyloP100		2.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.048
Sift	Benign	0.15	T
Sift4G	Benign	0.20	T
Polyphen		0.036	B
Vest4		0.19
MVP		0.48
MPC		0.078
ClinPred		0.014	T
GERP RS		3.0
Varity_R		0.039
gMVP		0.40
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs537610140; hg19: chr11-71819113; COSMIC: COSV105845969; COSMIC: COSV105845969;