chr11-72093668-C-T

Position:

• chr11-72093668-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_145309.6(LRRC51):​c.255C>T​(p.Asp85=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,200 control chromosomes in the GnomAD database, including 12 homozygotes. 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 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (12 hom.)
• Consequence: LRRC51 NM_145309.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.956

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:):

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-72093668-C-T is Benign according to our data. Variant chr11-72093668-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305986.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=0.956 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC51	NM_145309.6	c.255C>T	p.Asp85=	synonymous_variant	4/6	ENST00000289488.8
LRTOMT	NM_001145309.4	c.-149C>T		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC51	ENST00000289488.8	c.255C>T	p.Asp85=	synonymous_variant	4/6	1	NM_145309.6	P1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00830

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00311 AC: 783 AN: 251482 Hom.: 2 AF XY: 0.00326 AC XY: 443 AN XY: 135914

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00428

Gnomad FIN exome AF: 0.00952

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00275 AC: 4018 AN: 1461892 Hom.: 12 Cov.: 32 AF XY: 0.00278 AC XY: 2023 AN XY: 727248

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00402

Gnomad4 FIN exome AF: 0.00870

Gnomad4 NFE exome AF: 0.00260

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00228 AC: 348 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74464

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00830

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00241 Hom.: 0

Bravo AF: 0.00189

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 63 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LRRC51: BS2; LRTOMT: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 02, 2016

p.Asp85Asp in exon 4B of LRTOMT: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1% (63/6614) of F innish chromosomes and 0.3% (396/121398) total chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145851613). -

LRTOMT-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.57

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: rs145851613; hg19: chr11-71804714;