NM_001393500.2:c.253G>A

Variant names:

• chr11-72106204-G-A
• rs181092713
• NM_001393500.2:c.253G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001393500.2(TOMT):​c.253G>A​(p.Val85Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,491,510 control chromosomes in the GnomAD database, including 6 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).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.06
• Publications: 2 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001393500.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0081934035).
• BP6: Variant 11-72106204-G-A is Benign according to our data. Variant chr11-72106204-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44039.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00375 (571/152342) while in subpopulation AFR AF = 0.0133 (552/41574). AF 95% confidence interval is 0.0124. There are 4 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	NM_001393500.2	MANE Select	c.253G>A	p.Val85Ile	missense	Exon 1 of 3	NP_001380429.1
	LRTOMT	NM_001145308.5		c.352G>A	p.Val118Ile	missense	Exon 5 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.352G>A	p.Val118Ile	missense	Exon 7 of 9	NP_001138781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	ENST00000541899.3	TSL:5 MANE Select	c.253G>A	p.Val85Ile	missense	Exon 1 of 3	ENSP00000494667.1
	LRTOMT	ENST00000307198.11	TSL:2	c.352G>A	p.Val118Ile	missense	Exon 5 of 7	ENSP00000305742.7
	LRTOMT	ENST00000427369.6	TSL:1	n.*71G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000409403.2

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 570 AN: 152224 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00104 AC: 124 AN: 118756 AF XY: 0.000785

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.000423

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000212

Gnomad OTH exome AF: 0.000285

GnomAD4 exome AF: 0.000378 AC: 506 AN: 1339168 Hom.: 2 Cov.: 30 AF XY: 0.000338 AC XY: 221 AN XY: 653256

African (AFR) AF: 0.0147 AC: 450 AN: 30648

American (AMR) AF: 0.000430 AC: 14 AN: 32582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22684

East Asian (EAS) AF: 0.00 AC: 0 AN: 34948

South Asian (SAS) AF: 0.00 AC: 0 AN: 74138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35248

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5480

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1047744

Other (OTH) AF: 0.000682 AC: 38 AN: 55696

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152342 Hom.: 4 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74498

African (AFR) AF: 0.0133 AC: 552 AN: 41574

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00560 Hom.: 0

Bravo AF: 0.00422

ESP6500AA AF: 0.0152 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00140 AC: 35

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.028
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.094
MVP		0.11
MPC		0.054
ClinPred		0.017	T
GERP RS		1.4
PromoterAI		0.025	Neutral
Varity_R		0.12
gMVP		0.17
Mutation Taster		=99/1	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: rs181092713; hg19: chr11-71817250; COSMIC: COSV109415860; COSMIC: COSV109415860;