rs540371915

Positions:

• chr11-72108744-C-T

Variant summary

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

The NM_001393500.2(TOMT):​c.596C>T​(p.Ala199Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,550,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.19

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]

ANAPC15 (HGNC:):

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=0.06716108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.596C>T	p.Ala199Val	missense_variant	3/3	ENST00000541899.3	NP_001380429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3	c.596C>T	p.Ala199Val	missense_variant	3/3	5	NM_001393500.2	ENSP00000494667.1
LRTOMT	ENST00000307198.11	c.695C>T	p.Ala232Val	missense_variant	7/7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000337 AC: 52 AN: 154228 Hom.: 1 AF XY: 0.000342 AC XY: 28 AN XY: 81874

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000484 AC: 676 AN: 1398078 Hom.: 0 Cov.: 32 AF XY: 0.000481 AC XY: 332 AN XY: 689608

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000328

Gnomad4 FIN exome AF: 0.000104

Gnomad4 NFE exome AF: 0.000548

Gnomad4 OTH exome AF: 0.000500

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74510

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000352 Hom.: 0

Bravo AF: 0.000332

ExAC AF: 0.000151 AC: 4

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 13, 2022	BS1_supporting -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 12, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Ala232Val var iant in LRTOMT has been previously identified by our laboratory in 2 Caucasian i ndividuals with hearing loss, but a second variant affecting the other copy of t he gene was not identified in either individual and pathogenic variants in a dif ferent gene explained the hearing loss in one of them. This variant has also bee n identified in 2/7684 South Asian chromosomes and in 2/8160 European chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs540371915). The alanine (Ala) at position 232 is not highly conserved in ma mmals and evolutionary distant species, and 1 mammal (Chinese tree shrew) carrie s a valine (Val), raising the possibility that this change at this position may be tolerated. Additional computational prediction tools do not provide strong su pport for or against an impact to the protein. In summary, while the clinical si gnificance of the p.Ala323Val variant is uncertain, these data suggest that it i s more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T;.;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;N;.
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.040	D;D;.
Polyphen		0.0010	B;B;.
Vest4		0.083
MVP		0.76
MPC		0.12
ClinPred		0.070	T
GERP RS		4.6
Varity_R		0.092
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs540371915; hg19: chr11-71819790;