Variant 11-72106006-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001393500.2(TOMT):c.55C>T(p.Arg19Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,398,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

TOMT
NM_001393500.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

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:):

LRTOMT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TOMT	NM_001393500.2 linkuse as main transcript	c.55C>T	p.Arg19Trp	missense_variant	1/3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145309.4 linkuse as main transcript	c.154C>T	p.Arg52Trp	missense_variant	7/9		NP_001138781.1
LRTOMT	NM_001145308.5 linkuse as main transcript	c.154C>T	p.Arg52Trp	missense_variant	5/7		NP_001138780.1
LRTOMT	NM_001145310.4 linkuse as main transcript	c.84-50C>T		intron_variant			NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3 linkuse as main transcript	c.55C>T	p.Arg19Trp	missense_variant	1/3	5	NM_001393500.2	ENSP00000494667	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000130

AC:

AN:

153986

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

81756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000183

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000429

AC:

AN:

1398580

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689848

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000371

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 63

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000013, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.635, PP3_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

0.022

Eigen_PC

Benign

0.0067

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.5

L;L;.

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.8

N;N;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

0.99

D;D;.

Vest4

0.89

MutPred

0.52

Gain of catalytic residue at L50 (P = 0.0032);Gain of catalytic residue at L50 (P = 0.0032);.;

MVP

0.92

MPC

0.39

ClinPred

0.84

GERP RS

0.99

Varity_R

0.19

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over