chr11-72095011-G-C

Position:

• chr11-72095011-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_145309.6(LRRC51):​c.352G>C​(p.Gly118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,614,014 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (41 hom.)
• Consequence: LRRC51 NM_145309.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.56

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008438677).
• BP6: Variant 11-72095011-G-C is Benign according to our data. Variant chr11-72095011-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226718.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC51	NM_145309.6	c.352G>C	p.Gly118Arg	missense_variant	5/6	ENST00000289488.8	NP_660352.1
LRTOMT	NM_001145309.4	c.-52G>C		5_prime_UTR_variant	5/9		NP_001138781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC51	ENST00000289488.8	c.352G>C	p.Gly118Arg	missense_variant	5/6	1	NM_145309.6	ENSP00000289488	P1

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 688 AN: 152036 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00479 AC: 1205 AN: 251474 Hom.: 8 AF XY: 0.00489 AC XY: 665 AN XY: 135908

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00645 AC: 9425 AN: 1461860 Hom.: 41 Cov.: 31 AF XY: 0.00625 AC XY: 4542 AN XY: 727222

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.00736

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00452 AC: 688 AN: 152154 Hom.: 3 Cov.: 32 AF XY: 0.00471 AC XY: 350 AN XY: 74370

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.00582

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00521 Hom.: 2

Bravo AF: 0.00439

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00687 AC: 59

ExAC AF: 0.00493 AC: 598

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00735

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 63 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	LRRC51: BP4, BS2; LRTOMT: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Gly118Arg in Exon 05 of LRTOMT: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (43/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs149637884). -

LRTOMT-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 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_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.0072	T;T;T;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	.;.;.;.;.;.;.;D;D;D;D;.;D
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;M;M;.;M;M;M;M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N;N;N;N;N;N;N;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.69	.;.;N;.;N;N;N;N;N;.;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.17	.;.;T;.;T;T;T;T;T;.;T;.;T
Sift4G	Benign	0.50	.;.;T;.;T;T;T;T;T;T;T;.;T
Polyphen		0.010	B;B;B;B;B;.;B;.;B;B;B;.;.
Vest4		0.37, 0.37, 0.28, 0.15, 0.37, 0.38
MutPred		0.38		Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);.;Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);.;Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);
MVP		0.48
ClinPred		0.0033	T
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs149637884; hg19: chr11-71806057;