Genetic Variant ENST00000307198.11:c.85G>C (chr11-72105937-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000307198.11(LRTOMT):c.85G>C(p.Ala29Pro) variant causes a missense, splice region 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. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A29T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LRTOMT
ENST00000307198.11 missense, splice_region

Scores

Splicing: ADA: 0.00002230

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.325

Publications

4 publications found

Variant links:

Genes affected

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 links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08584091).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307198.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOMT	NM_001393500.2	MANE Select	c.-15G>C		5_prime_UTR	Exon 1 of 3	NP_001380429.1	A0A2R8Y5M8
LRTOMT	NM_001145308.5		c.85G>C	p.Ala29Pro	missense splice_region	Exon 5 of 7	NP_001138780.1
LRTOMT	NM_001145309.4		c.85G>C	p.Ala29Pro	missense splice_region	Exon 7 of 9	NP_001138781.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRTOMT	ENST00000307198.11	TSL:2	c.85G>C	p.Ala29Pro	missense splice_region	Exon 5 of 7	ENSP00000305742.7
TOMT	ENST00000541899.3	TSL:5 MANE Select	c.-15G>C		5_prime_UTR	Exon 1 of 3	ENSP00000494667.1	A0A2R8Y5M8
LRTOMT	ENST00000427369.6	TSL:1	n.488G>C		splice_region 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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

3.4

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.036

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.26

M_CAP

Benign

0.057

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.55

PhyloP100

-0.33

PrimateAI

Benign

0.35

PROVEAN

Benign

0.040

REVEL

Benign

0.24

Sift

Uncertain

0.023

Sift4G

Uncertain

0.035

Polyphen

0.38

Vest4

0.27

MutPred

0.46

Loss of sheet (P = 0.0126)

MVP

0.43

MPC

0.10

ClinPred

0.092

GERP RS

0.91

PromoterAI

-0.0026

Neutral

(source)

Varity_R

0.064

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over