Genetic Variant NM_003667.4:c.702C>A (chr12-71556676-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003667.4(LGR5):c.702C>A(p.His234Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LGR5
NM_003667.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.55

Variant links:

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]

LGR5 links:

LOC105369833 (HGNC:):

LOC105369833 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32078254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGR5	NM_003667.4 link	c.702C>A	p.His234Gln	missense_variant	Exon 6 of 18	ENST00000266674.10	NP_003658.1	O75473-1A0A0A8K8C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LGR5	ENST00000266674.10 link	c.702C>A	p.His234Gln	missense_variant	Exon 6 of 18	1	NM_003667.4	ENSP00000266674.4	O75473-1
LGR5	ENST00000540815.2 link	c.702C>A	p.His234Gln	missense_variant	Exon 6 of 17	1		ENSP00000441035.2	O75473-2
LGR5	ENST00000536515.5 link	c.486C>A	p.His162Gln	missense_variant	Exon 5 of 17	1		ENSP00000443033.1	O75473-3
LGR5	ENST00000550851.5 link	n.799C>A		non_coding_transcript_exon_variant	Exon 6 of 20	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251296

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725534

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.16

T;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.0093

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.59

T;T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;.;N

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Benign

0.11

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.60

P;.;B

Vest4

0.30

MutPred

0.32

Gain of catalytic residue at F230 (P = 0.0688);.;Gain of catalytic residue at F230 (P = 0.0688);

MVP

0.72

MPC

0.34

ClinPred

0.89

GERP RS

4.7

Varity_R

0.68

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over