12-71584007-T-C

Variant names:

• chr12-71584007-T-C
• rs17109924
• NM_003667.4:c.1997T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003667.4(LGR5):​c.1997T>C​(p.Val666Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,614,112 control chromosomes in the GnomAD database, including 5,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.084 (619 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4469 hom.)
• Consequence: LGR5 NM_003667.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 28 publications found

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]

ENSG00000288530 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002444744).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003667.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGR5	NM_003667.4	MANE Select	c.1997T>C	p.Val666Ala	missense	Exon 18 of 18	NP_003658.1
	LGR5	NM_001277226.2		c.1925T>C	p.Val642Ala	missense	Exon 17 of 17	NP_001264155.1
	LGR5	NM_001277227.2		c.1781T>C	p.Val594Ala	missense	Exon 17 of 17	NP_001264156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGR5	ENST00000266674.10	TSL:1 MANE Select	c.1997T>C	p.Val666Ala	missense	Exon 18 of 18	ENSP00000266674.4
	LGR5	ENST00000540815.2	TSL:1	c.1925T>C	p.Val642Ala	missense	Exon 17 of 17	ENSP00000441035.2
	LGR5	ENST00000536515.5	TSL:1	c.1781T>C	p.Val594Ala	missense	Exon 17 of 17	ENSP00000443033.1

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12843 AN: 152118 Hom.: 617 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0864

Gnomad FIN AF: 0.0927

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0787

Gnomad OTH AF: 0.0736

GnomAD2 exomes AF: 0.0739 AC: 18592 AN: 251422 AF XY: 0.0740

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0706

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.00533

Gnomad FIN exome AF: 0.0929

Gnomad NFE exome AF: 0.0740

Gnomad OTH exome AF: 0.0765

GnomAD4 exome AF: 0.0756 AC: 110460 AN: 1461876 Hom.: 4469 Cov.: 33 AF XY: 0.0756 AC XY: 55000 AN XY: 727240

African (AFR) AF: 0.114 AC: 3808 AN: 33478

American (AMR) AF: 0.0706 AC: 3158 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0696 AC: 1819 AN: 26136

East Asian (EAS) AF: 0.00617 AC: 245 AN: 39700

South Asian (SAS) AF: 0.0871 AC: 7510 AN: 86258

European-Finnish (FIN) AF: 0.0964 AC: 5149 AN: 53418

Middle Eastern (MID) AF: 0.0643 AC: 371 AN: 5768

European-Non Finnish (NFE) AF: 0.0755 AC: 83960 AN: 1112002

Other (OTH) AF: 0.0735 AC: 4440 AN: 60392

GnomAD4 genome AF: 0.0845 AC: 12857 AN: 152236 Hom.: 619 Cov.: 32 AF XY: 0.0847 AC XY: 6301 AN XY: 74428

African (AFR) AF: 0.107 AC: 4462 AN: 41526

American (AMR) AF: 0.0743 AC: 1137 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3468

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5182

South Asian (SAS) AF: 0.0864 AC: 417 AN: 4824

European-Finnish (FIN) AF: 0.0927 AC: 982 AN: 10598

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0787 AC: 5354 AN: 68018

Other (OTH) AF: 0.0728 AC: 154 AN: 2114

Alfa AF: 0.0773 Hom.: 2081

Bravo AF: 0.0821

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0737 AC: 284

ESP6500AA AF: 0.103 AC: 456

ESP6500EA AF: 0.0764 AC: 657

ExAC AF: 0.0753 AC: 9146

Asia WGS AF: 0.0600 AC: 208 AN: 3478

EpiCase AF: 0.0737

EpiControl AF: 0.0698

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0034
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.45	T
Sift4G	Benign	0.53	T
Polyphen		0.035	B
Vest4		0.10
MPC		0.070
ClinPred		0.0097	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.63
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs17109924; hg19: chr12-71977787; COSMIC: COSV57004115; COSMIC: COSV57004115;