rs149637884

Variant names:

• chr11-72095011-G-C
• rs149637884
• NM_145309.6:c.352G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-72095011-G-C
• chr11-72095011-G-A

Variant summary

Our verdict is Benign. The variant received -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. 15/19 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
• Publications: 4 publications found

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 -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 VariationId is 226718.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145309.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC51	NM_145309.6	MANE Select	c.352G>C	p.Gly118Arg	missense	Exon 5 of 6	NP_660352.1	Q96E66-1
	LRRC51	NM_001318803.2		c.352G>C	p.Gly118Arg	missense	Exon 5 of 6	NP_001305732.1	Q96E66-1
	LRRC51	NM_001205138.4		c.298G>C	p.Gly100Arg	missense	Exon 4 of 5	NP_001192067.1	Q96E66-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC51	ENST00000289488.8	TSL:1 MANE Select	c.352G>C	p.Gly118Arg	missense	Exon 5 of 6	ENSP00000289488.2	Q96E66-1
	LRRC51	ENST00000541614.5	TSL:1	c.352G>C	p.Gly118Arg	missense	Exon 4 of 5	ENSP00000438522.1	Q96E66-2
	LRRC51	ENST00000324866.11	TSL:1	c.352G>C	p.Gly118Arg	missense	Exon 5 of 5	ENSP00000440693.1	Q96E66-3

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

GnomAD2 exomes AF: 0.00479 AC: 1205 AN: 251474 AF XY: 0.00489

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 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

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86228

European-Finnish (FIN) AF: 0.0114 AC: 608 AN: 53420

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.00736 AC: 8179 AN: 1112008

Other (OTH) AF: 0.00581 AC: 351 AN: 60396

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

African (AFR) AF: 0.00154 AC: 64 AN: 41508

American (AMR) AF: 0.00595 AC: 91 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00582 AC: 396 AN: 67996

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal recessive nonsyndromic hearing loss 63 (3)
-	-	2	not provided (2)
-	-	1	LRTOMT-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Benign	0.50	T
Polyphen		0.010	B
Vest4		0.37
MutPred		0.38		Gain of MoRF binding (P = 0.02)
MVP		0.48
ClinPred		0.0033	T
GERP RS		3.2
Mutation Taster		=295/5	polymorphism

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

Other links and lift over

dbSNP: rs149637884; hg19: chr11-71806057;