11-72093467-G-A

Variant names:

• chr11-72093467-G-A
• rs2250866
• NM_145309.6:c.83-29G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_145309.6(LRRC51):​c.83-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0747 in 1,588,678 control chromosomes in the GnomAD database, including 6,427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.11 (1271 hom., cov: 32)
  • Exomes 𝑓: 0.071 (5156 hom.)
• Consequence: LRRC51 NM_145309.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0960

Genes affected

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]

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]

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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-72093467-G-A is Benign according to our data. Variant chr11-72093467-G-A is described in ClinVar as [Benign]. Clinvar id is 682806.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC51	NM_145309.6	c.83-29G>A		intron_variant	Intron 3 of 5	ENST00000289488.8	NP_660352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC51	ENST00000289488.8	c.83-29G>A		intron_variant	Intron 3 of 5	1	NM_145309.6	ENSP00000289488.2
LRTOMT	ENST00000307198.11	c.-321-29G>A		intron_variant	Intron 1 of 6	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17314 AN: 152066 Hom.: 1270 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0899

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0966

GnomAD2 exomes AF: 0.106 AC: 22665 AN: 214540 AF XY: 0.104

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.0934

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.0734

Gnomad NFE exome AF: 0.0562

Gnomad OTH exome AF: 0.0872

GnomAD4 exome AF: 0.0706 AC: 101401 AN: 1436492 Hom.: 5156 Cov.: 31 AF XY: 0.0728 AC XY: 51892 AN XY: 712696

Gnomad4 AFR exome AF: 0.189 AC: 6197 AN: 32852

Gnomad4 AMR exome AF: 0.145 AC: 5870 AN: 40560

Gnomad4 ASJ exome AF: 0.0900 AC: 2304 AN: 25612

Gnomad4 EAS exome AF: 0.224 AC: 8663 AN: 38622

Gnomad4 SAS exome AF: 0.155 AC: 12931 AN: 83468

Gnomad4 FIN exome AF: 0.0702 AC: 3668 AN: 52260

Gnomad4 NFE exome AF: 0.0513 AC: 56402 AN: 1098722

Gnomad4 Remaining exome AF: 0.0832 AC: 4951 AN: 59502

GnomAD4 genome AF: 0.114 AC: 17342 AN: 152186 Hom.: 1271 Cov.: 32 AF XY: 0.119 AC XY: 8843 AN XY: 74412

Gnomad4 AFR AF: 0.185 AC: 0.185186 AN: 0.185186

Gnomad4 AMR AF: 0.172 AC: 0.172163 AN: 0.172163

Gnomad4 ASJ AF: 0.0899 AC: 0.0899135 AN: 0.0899135

Gnomad4 EAS AF: 0.231 AC: 0.230873 AN: 0.230873

Gnomad4 SAS AF: 0.161 AC: 0.161136 AN: 0.161136

Gnomad4 FIN AF: 0.0682 AC: 0.0681818 AN: 0.0681818

Gnomad4 NFE AF: 0.0550 AC: 0.0549659 AN: 0.0549659

Gnomad4 OTH AF: 0.0946 AC: 0.0946074 AN: 0.0946074

Alfa AF: 0.0834 Hom.: 169

Bravo AF: 0.122

Asia WGS AF: 0.177 AC: 618 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.54
BranchPoint Hunter		0.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2250866; hg19: chr11-71804513; COSMIC: COSV53825510; COSMIC: COSV53825510;