11-72106043-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001393500.2(TOMT):c.92T>G(p.Val31Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000438 in 1,550,986 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 1 hom. )

Consequence

TOMT
NM_001393500.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.86

Publications

1 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMT	NM_001393500.2 link	c.92T>G	p.Val31Gly	missense_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5 link	c.191T>G	p.Val64Gly	missense_variant	Exon 5 of 7		NP_001138780.1	Q8WZ04-1
LRTOMT	NM_001145309.4 link	c.191T>G	p.Val64Gly	missense_variant	Exon 7 of 9		NP_001138781.1	Q8WZ04-1
LRTOMT	NM_001145310.4 link	c.84-13T>G		intron_variant	Intron 6 of 8		NP_001138782.1	Q8WZ04-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3 link	c.92T>G	p.Val31Gly	missense_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1		A0A2R8Y5M8
LRTOMT	ENST00000307198.11 link	c.191T>G	p.Val64Gly	missense_variant	Exon 5 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000388

AC:

AN:

154528

AF XY:

0.0000487

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000811

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000333

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000436

AC:

AN:

1398794

Hom.:

Cov.:

AF XY:

0.0000464

AC XY:

AN XY:

689952

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31594

American (AMR)

AF:

0.0000840

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000139

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48750

Middle Eastern (MID)

AF:

0.00107

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1078968

Other (OTH)

AF:

0.0000517

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41528

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000580

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000116

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Val64Gly variant in LRTOMT has not been previously reported in individuals w ith hearing loss or in large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, the clinical significance of the Val64Gly variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.191T>G (p.V64G) alteration is located in exon 5 (coding exon 3) of the LRTOMT gene. This alteration results from a T to G substitution at nucleotide position 191, causing the valine (V) at amino acid position 64 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 63

Uncertain:1

May 31, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1

Apr 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 179867). This variant has not been reported in the literature in individuals affected with LRTOMT-related conditions. This variant is present in population databases (rs574631765, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 64 of the LRTOMT protein (p.Val64Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.52

T;.;T

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.9

L;L;.

PhyloP100

6.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

N;N;.

REVEL

Pathogenic

0.71

Sift

Benign

0.051

T;T;.

Sift4G

Benign

0.26

T;T;.

Polyphen

1.0

D;D;.

Vest4

0.68

MutPred

0.43

Loss of stability (P = 0.0041);Loss of stability (P = 0.0041);.;

MVP

0.86

MPC

0.44

ClinPred

0.83

GERP RS

4.4

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.29

gMVP

0.83

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over