NM_145309.6:c.37G>A

Variant names:

• chr11-72089120-G-A
• rs146942815
• NM_145309.6:c.37G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_145309.6(LRRC51):​c.37G>A​(p.Glu13Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00701 in 1,614,088 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (50 hom.)
• Consequence: LRRC51 NM_145309.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.22
• Publications: 13 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007390946).
• BP6: Variant 11-72089120-G-A is Benign according to our data. Variant chr11-72089120-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2642116.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.37G>A	p.Glu13Lys	missense	Exon 3 of 6	NP_660352.1	Q96E66-1
	LRRC51	NM_001318803.2		c.37G>A	p.Glu13Lys	missense	Exon 3 of 6	NP_001305732.1	Q96E66-1
	LRRC51	NM_001145307.5		c.37G>A	p.Glu13Lys	missense	Exon 3 of 6	NP_001138779.1	Q96E66-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC51	ENST00000289488.8	TSL:1 MANE Select	c.37G>A	p.Glu13Lys	missense	Exon 3 of 6	ENSP00000289488.2	Q96E66-1
	LRRC51	ENST00000541614.5	TSL:1	c.37G>A	p.Glu13Lys	missense	Exon 2 of 5	ENSP00000438522.1	Q96E66-2
	LRRC51	ENST00000324866.11	TSL:1	c.37G>A	p.Glu13Lys	missense	Exon 3 of 5	ENSP00000440693.1	Q96E66-3

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 751 AN: 152110 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00463 AC: 1165 AN: 251474 AF XY: 0.00486

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.00704

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00722 AC: 10561 AN: 1461860 Hom.: 50 Cov.: 31 AF XY: 0.00711 AC XY: 5169 AN XY: 727230

African (AFR) AF: 0.00137 AC: 46 AN: 33480

American (AMR) AF: 0.00237 AC: 106 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 338 AN: 26136

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

South Asian (SAS) AF: 0.00103 AC: 89 AN: 86256

European-Finnish (FIN) AF: 0.00408 AC: 218 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00838 AC: 9314 AN: 1111986

Other (OTH) AF: 0.00732 AC: 442 AN: 60396

GnomAD4 genome AF: 0.00493 AC: 750 AN: 152228 Hom.: 2 Cov.: 32 AF XY: 0.00466 AC XY: 347 AN XY: 74440

African (AFR) AF: 0.00144 AC: 60 AN: 41526

American (AMR) AF: 0.00393 AC: 60 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00735 AC: 500 AN: 68006

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00636 Hom.: 11

Bravo AF: 0.00465

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00629 AC: 54

ExAC AF: 0.00481 AC: 584

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00634

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.080
Sift	Benign	0.074	T
Sift4G	Benign	0.25	T
Polyphen		0.80	P
Vest4		0.60
MVP		0.55
ClinPred		0.023	T
GERP RS		4.8
Mutation Taster		=280/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146942815; hg19: chr11-71800166; COSMIC: COSV106089674;