12-71577986-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003667.4(LGR5):c.1270C>G(p.Leu424Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 1,610,642 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (76 hom.)
• Consequence: LGR5 NM_003667.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.971

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]

LOC124902963 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007958859).
• BP6: Variant 12-71577986-C-G is Benign according to our data. Variant chr12-71577986-C-G is described in ClinVar as [Benign]. Clinvar id is 711464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00488 (743/152292) while in subpopulation SAS AF= 0.0228 (110/4826). AF 95% confidence interval is 0.0193. There are 9 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGR5	NM_003667.4	c.1270C>G	p.Leu424Val	missense_variant	14/18	ENST00000266674.10
LOC124902963	XR_007063365.1	n.126-955G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGR5	ENST00000266674.10	c.1270C>G	p.Leu424Val	missense_variant	14/18	1	NM_003667.4	P1

Frequencies

GnomAD3 genomes AF: 0.00486 AC: 740 AN: 152174 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00651

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00687 AC: 1726 AN: 251232 Hom.: 11 AF XY: 0.00789 AC XY: 1071 AN XY: 135794

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0210

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.00722

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00650 AC: 9480 AN: 1458350 Hom.: 76 Cov.: 28 AF XY: 0.00708 AC XY: 5140 AN XY: 725772

Gnomad4 AFR exome AF: 0.000719

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000996

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.00547

Gnomad4 NFE exome AF: 0.00601

Gnomad4 OTH exome AF: 0.00721

GnomAD4 genome AF: 0.00488 AC: 743 AN: 152292 Hom.: 9 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74472

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.00650

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00682 Hom.: 5

Bravo AF: 0.00406

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00740 AC: 898

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.00890

EpiControl AF: 0.00794

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;D;D
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;D;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.76
MVP		0.94
MPC		0.34
ClinPred		0.062	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs138215571; hg19: chr12-71971766; COSMIC: COSV105072003; COSMIC: COSV105072003;