12-71553245-A-C

Variant names:

• chr12-71553245-A-C
• rs768780796
• NM_003667.4:c.601A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003667.4(LGR5):​c.601A>C​(p.Ile201Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LGR5 NM_003667.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.37
• Publications: 0 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]

LOC105369833 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGR5	NM_003667.4	MANE Select	c.601A>C	p.Ile201Leu	missense	Exon 5 of 18	NP_003658.1	O75473-1
	LGR5	NM_001277226.2		c.601A>C	p.Ile201Leu	missense	Exon 5 of 17	NP_001264155.1	O75473-2
	LGR5	NM_001277227.2		c.429-3374A>C		intron	N/A	NP_001264156.1	O75473-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGR5	ENST00000266674.10	TSL:1 MANE Select	c.601A>C	p.Ile201Leu	missense	Exon 5 of 18	ENSP00000266674.4	O75473-1
	LGR5	ENST00000540815.2	TSL:1	c.601A>C	p.Ile201Leu	missense	Exon 5 of 17	ENSP00000441035.2	O75473-2
	LGR5	ENST00000536515.5	TSL:1	c.429-3374A>C		intron	N/A	ENSP00000443033.1	O75473-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251106 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.1	L
PhyloP100		6.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.10	T
Polyphen		0.97	D
Vest4		0.69
MutPred		0.50		Gain of catalytic residue at D203 (P = 0)
MVP		0.96
MPC		0.085
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.30
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs768780796; hg19: chr12-71947025;