rs17109924

chr12-71584007-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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=0.002444744).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGR5	NM_003667.4	c.1997T>C	p.Val666Ala	missense_variant	18/18	ENST00000266674.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGR5	ENST00000266674.10	c.1997T>C	p.Val666Ala	missense_variant	18/18	1	NM_003667.4	P1
LGR5	ENST00000540815.2	c.1925T>C	p.Val642Ala	missense_variant	17/17	1
LGR5	ENST00000536515.5	c.1781T>C	p.Val594Ala	missense_variant	17/17	1
LGR5	ENST00000550851.5	n.2283+95T>C		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.0739 AC: 18592 AN: 251422 Hom.: 792 AF XY: 0.0740 AC XY: 10056 AN XY: 135874

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 SAS exome AF: 0.0885

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

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.0706

Gnomad4 ASJ exome AF: 0.0696

Gnomad4 EAS exome AF: 0.00617

Gnomad4 SAS exome AF: 0.0871

Gnomad4 FIN exome AF: 0.0964

Gnomad4 NFE exome AF: 0.0755

Gnomad4 OTH exome AF: 0.0735

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

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0743

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.0864

Gnomad4 FIN AF: 0.0927

Gnomad4 NFE AF: 0.0787

Gnomad4 OTH AF: 0.0728

Alfa AF: 0.0753 Hom.: 1017

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 v4.3

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;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.035	B;.;B
Vest4		0.10
MPC		0.070
ClinPred		0.0097	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs17109924; hg19: chr12-71977787; COSMIC: COSV57004115; COSMIC: COSV57004115;