rs61737422

chr12-71584663-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003667.4(LGR5):c.2653G>A(p.Val885Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,614,088 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: LGR5 NM_003667.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370

Genes affected

LGR5 (HGNC:4504): (leucine rich repeat containing G protein-coupled receptor 5) The protein encoded by this gene is a leucine-rich repeat-containing receptor (LGR) and member of the G protein-coupled, 7-transmembrane receptor (GPCR) superfamily. The encoded protein is a receptor for R-spondins and is involved in the canonical Wnt signaling pathway. This protein plays a role in the formation and maintenance of adult intestinal stem cells during postembryonic development. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023320317).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1539/152230) while in subpopulation AFR AF= 0.0345 (1432/41514). AF 95% confidence interval is 0.033. There are 19 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGR5	NM_003667.4	c.2653G>A	p.Val885Met	missense_variant	18/18	ENST00000266674.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGR5	ENST00000266674.10	c.2653G>A	p.Val885Met	missense_variant	18/18	1	NM_003667.4	P1
LGR5	ENST00000540815.2	c.2581G>A	p.Val861Met	missense_variant	17/17	1
LGR5	ENST00000536515.5	c.2437G>A	p.Val813Met	missense_variant	17/17	1
LGR5	ENST00000550851.5	n.2452G>A		non_coding_transcript_exon_variant	20/20	2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1536 AN: 152112 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00246 AC: 619 AN: 251440 Hom.: 11 AF XY: 0.00169 AC XY: 230 AN XY: 135888

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00106 AC: 1556 AN: 1461858 Hom.: 27 Cov.: 32 AF XY: 0.000903 AC XY: 657 AN XY: 727230

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.0101 AC: 1539 AN: 152230 Hom.: 19 Cov.: 32 AF XY: 0.00967 AC XY: 720 AN XY: 74426

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00182 Hom.: 6

Bravo AF: 0.0116

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.43
Dann	Benign	0.32
DEOGEN2	Benign	0.081	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.52	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.51	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0070	B;.;B
Vest4		0.053
MVP		0.38
MPC		0.052
ClinPred		0.0038	T
GERP RS		-5.2
Varity_R		0.027
gMVP		0.39

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: rs61737422; hg19: chr12-71978443; COSMIC: COSV99030809; COSMIC: COSV99030809;