11-72106094-G-A

Position:

chr11-72106094-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong

The NM_001393500.2(TOMT):c.143G>A(p.Arg48Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,549,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

TOMT
NM_001393500.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.56

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 Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-72106093-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

PP5

Variant 11-72106094-G-A is Pathogenic according to our data. Variant chr11-72106094-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72106094-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TOMT	NM_001393500.2 linkuse as main transcript	c.143G>A	p.Arg48Gln	missense_variant	1/3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145309.4 linkuse as main transcript	c.242G>A	p.Arg81Gln	missense_variant	7/9		NP_001138781.1
LRTOMT	NM_001145308.5 linkuse as main transcript	c.242G>A	p.Arg81Gln	missense_variant	5/7		NP_001138780.1
LRTOMT	NM_001145310.4 linkuse as main transcript	c.122G>A	p.Arg41Gln	missense_variant	7/9		NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3 linkuse as main transcript	c.143G>A	p.Arg48Gln	missense_variant	1/3	5	NM_001393500.2	ENSP00000494667	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000259

AC:

AN:

154430

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

82048

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000498

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000444

AC:

AN:

1397156

Hom.:

Cov.:

AF XY:

0.0000508

AC XY:

AN XY:

689230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000519

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000575

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 63

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant was co-segregated with Deafness, autosomal recessive 63 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 18953341, PP1_S). It has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 18953341,PM3_P). A different missense change at the same codon has been reported to be associated with LRTOMT related disorder (PMID:22903915, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.701, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000026, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 09, 2018

The p.Arg81Gln variant in LRTOMT has been reported in 16 North African (Tunisian and Moroccan) probands with hearing loss, and segregated with hearing loss in > 20 family members, all of whom were homozygous for the variant (Ahmed 2008, Char if 2008). The variant was detected in 5/430 (1.2%) ethnically matched control ch romosomes, however its frequency in the probands (13.8%, 32/232 chromosomes) is significantly higher, which supports a causative role for the variant, and sugge sts that the variant may represent a founder mutation in these populations. In a ddition, computational prediction tools and conservation analyses suggest that t his variant may impact the protein. The variant has also been identified in 3/57 674 European chromosomes by the genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org/). In summary, this variant meets criteria to be classifie d as pathogenic for hearing loss in an autosomal recessive manner based upon seg regation studies and enrichment in cases. ACMG/AMP criteria applied: PS4, PP1_St rong, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.0

M;M;.

MutationTaster

Benign

0.85

A;A;A;A

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.055

T;T;.

Polyphen

1.0

D;D;.

Vest4

0.59

MVP

0.97

MPC

0.41

ClinPred

0.80

GERP RS

4.6

Varity_R

0.68

gMVP

0.70

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

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