Genetic Variant TOMT:p.Leu33Met (chr11-72106048-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001145308.5(LRTOMT):c.196C>A(p.Leu66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L66V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

LRTOMT
NM_001145308.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

Publications

0 publications found

Variant links:

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]

TOMT links:

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]

LRTOMT Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 63
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LRTOMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26846084).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145308.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TOMT	NM_001393500.2	MANE Select	c.97C>A	p.Leu33Met	missense	Exon 1 of 3	NP_001380429.1
LRTOMT	NM_001145308.5		c.196C>A	p.Leu66Met	missense	Exon 5 of 7	NP_001138780.1
LRTOMT	NM_001145309.4		c.196C>A	p.Leu66Met	missense	Exon 7 of 9	NP_001138781.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TOMT	ENST00000541899.3	TSL:5 MANE Select	c.97C>A	p.Leu33Met	missense	Exon 1 of 3	ENSP00000494667.1
LRTOMT	ENST00000307198.11	TSL:2	c.196C>A	p.Leu66Met	missense	Exon 5 of 7	ENSP00000305742.7
LRTOMT	ENST00000427369.6	TSL:1	n.599C>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000409403.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.073

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.6

PhyloP100

1.4

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.19

REVEL

Benign

0.23

Sift

Benign

0.051

Sift4G

Benign

0.14

Polyphen

0.0060

Vest4

0.23

MutPred

0.37

Gain of helix (P = 0.0078)

MVP

0.58

MPC

0.26

ClinPred

0.82

GERP RS

3.5

PromoterAI

-0.0064

Neutral

(source)

Varity_R

0.072

gMVP

0.54

Mutation Taster

=30/70

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over