11-72093528-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001145308.5(LRTOMT):​c.-289C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

LRTOMT
NM_001145308.5 5_prime_UTR_premature_start_codon_gain

Scores

2
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.83
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]
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_addAF=-0.39036).
BP6
Variant 11-72093528-C-T is Benign according to our data. Variant chr11-72093528-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228838.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRRC51NM_145309.6 linkc.115C>T p.Arg39* stop_gained Exon 4 of 6 ENST00000289488.8 NP_660352.1 Q96E66-1A0A024R5L6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRTOMTENST00000307198 linkc.-289C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 2 of 7 2 ENSP00000305742.7
LRRC51ENST00000289488.8 linkc.115C>T p.Arg39* stop_gained Exon 4 of 6 1 NM_145309.6 ENSP00000289488.2 Q96E66-1
LRTOMTENST00000307198 linkc.-289C>T 5_prime_UTR_variant Exon 2 of 7 2 ENSP00000305742.7

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152216
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
53
AN:
250986
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135682
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00136
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:
0.0000441
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000732
AC:
107
AN:
1461664
Hom.:
0
Cov.:
32
AF XY:
0.0000468
AC XY:
34
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00125
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152216
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000353
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.000173
AC:
21
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 10, 2015The p.Arg39X variant in LRTOMT (NM_001145307.1) has not been previously reported in individuals with hearing loss, but has been identified in 0.15% (16/10440) o f Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs780299621). This variant leads to a premature terminatio n codon at position 39 in the NM_001145307.1 transcript of LRTOMT. However, in s everal alternate transcripts of the LRTOMT gene, the variant lies in the 5'UTR a nd its impact on these transcripts is unknown. In addition, the majority of repo rted pathogenic LRTOMT variants are located in the coding exons of these alterna te transcripts, which correspond to noncoding regions in the NM_001145307.1 tran script. Therefore, there is insufficient evidence to determine whether loss of f unction variants affecting the NM_001145307.1 transcript of LRTOMT are causative for hearing loss, and the impact of this variant on alternate transcripts of LR TOMT is not known. In summary, the clinical significance of the p.Arg39X variant in the NM_001145307.1 transcript of LRTOMT is uncertain. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 24, 2021See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.37
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Benign
0.049
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.79
D
Vest4
0.42, 0.43, 0.42, 0.39, 0.41
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs780299621; hg19: chr11-71804574; API