11-72093694-T-C

Variant names:

Variant summary

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

The NM_001145308.5(LRTOMT):c.-123T>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000595 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

LRTOMT
NM_001145308.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

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:

LRRC51 (HGNC:55526): (leucine rich repeat containing 51) This gene belongs to the leucine-rich repeat containing family. The encoded protein contains a transmembrane domain and two leucine-rich repeat domains. Unlike in mouse and other mammals, readthrough transcription is observed in primates between this gene and the adjacent transmembrane O-methyltransferase (Tomt) gene. Previously, this locus was annotated as a single gene representing the readthrough transcripts as well as the two different transcript species that encoded different proteins. It has since been split into three genes, including the two stand-alone genes and a third gene representing the readthrough transcription. [provided by RefSeq, Feb 2022]

LRRC51 links:

LAMTOR1 (HGNC:26068): (late endosomal/lysosomal adaptor, MAPK and MTOR activator 1) Enables GTPase binding activity. Contributes to guanyl-nucleotide exchange factor activity and molecular adaptor activity. Involved in several processes, including cholesterol homeostasis; positive regulation of TOR signaling; and regulation of cholesterol transport. Located in lysosome. Part of Ragulator complex. [provided by Alliance of Genome Resources, Apr 2022]

LAMTOR1 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 rank	MANE	Protein	UniProt
LRRC51	NM_145309.6 link	c.281T>C	p.Ile94Thr	missense_variant	Exon 4 of 6	ENST00000289488.8	NP_660352.1	Q96E66-1A0A024R5L6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRTOMT	ENST00000307198 link	c.-123T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7	2		ENSP00000305742.7
LRRC51	ENST00000289488.8 link	c.281T>C	p.Ile94Thr	missense_variant	Exon 4 of 6	1	NM_145309.6	ENSP00000289488.2	Q96E66-1
LRTOMT	ENST00000307198 link	c.-123T>C		5_prime_UTR_variant	Exon 2 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251452

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000296

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000893

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;T;T;.;.;T;.;.;.;.;T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

.;.;.;.;.;.;.;D;D;D;D;D;.;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.61

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Pathogenic

3.4

M;M;M;M;.;M;M;M;.;M;.;M;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.7

.;.;D;.;D;D;D;D;D;D;.;D;.;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

.;.;D;.;D;D;D;D;D;D;.;D;.;D

Sift4G

Uncertain

0.0020

.;.;D;.;D;D;D;D;D;D;D;D;.;D

Polyphen

1.0

D;D;D;D;D;.;D;.;.;D;D;D;.;.

Vest4

0.89, 0.90, 0.88, 0.89, 0.86, 0.90, 0.89

MVP

0.85

ClinPred

0.33

GERP RS

5.3

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