chr12-71535176-C-T

Position:

• chr12-71535176-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003667.4(LGR5):​c.418C>T​(p.Leu140Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,450,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LGR5 NM_003667.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGR5	NM_003667.4	c.418C>T	p.Leu140Phe	missense_variant	4/18	ENST00000266674.10	NP_003658.1
LOC105369833	XR_001749200.2	n.119-1120G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGR5	ENST00000266674.10	c.418C>T	p.Leu140Phe	missense_variant	4/18	1	NM_003667.4	ENSP00000266674	P1
LGR5	ENST00000540815.2	c.418C>T	p.Leu140Phe	missense_variant	4/17	1		ENSP00000441035
LGR5	ENST00000536515.5	c.418C>T	p.Leu140Phe	missense_variant	4/17	1		ENSP00000443033
LGR5	ENST00000550851.5	n.515C>T		non_coding_transcript_exon_variant	4/20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1450450 Hom.: 0 Cov.: 26 AF XY: 0.00000830 AC XY: 6 AN XY: 722480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000635

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2023

The c.418C>T (p.L140F) alteration is located in exon 4 (coding exon 4) of the LGR5 gene. This alteration results from a C to T substitution at nucleotide position 418, causing the leucine (L) at amino acid position 140 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.5	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.58
MutPred		0.74		Gain of catalytic residue at N136 (P = 0.0174);Gain of catalytic residue at N136 (P = 0.0174);Gain of catalytic residue at N136 (P = 0.0174);
MVP		0.97
MPC		0.35
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.69

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: rs1876525726; hg19: chr12-71928956;