chr12-71553284-G-A

Position:

• chr12-71553284-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003667.4(LGR5):​c.640G>A​(p.Val214Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,612,488 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00057 (5 hom.)
• Consequence: LGR5 NM_003667.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGR5	NM_003667.4	c.640G>A	p.Val214Ile	missense_variant	5/18	ENST00000266674.10	NP_003658.1
LOC105369833	XR_001749200.2	n.118+18349C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGR5	ENST00000266674.10	c.640G>A	p.Val214Ile	missense_variant	5/18	1	NM_003667.4	ENSP00000266674	P1
LGR5	ENST00000540815.2	c.640G>A	p.Val214Ile	missense_variant	5/17	1		ENSP00000441035
LGR5	ENST00000536515.5	c.429-3335G>A		intron_variant		1		ENSP00000443033
LGR5	ENST00000550851.5	n.737G>A		non_coding_transcript_exon_variant	5/20	2

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 151968 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000644 AC: 161 AN: 250156 Hom.: 1 AF XY: 0.000680 AC XY: 92 AN XY: 135216

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000790

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000568 AC: 830 AN: 1460402 Hom.: 5 Cov.: 30 AF XY: 0.000612 AC XY: 445 AN XY: 726620

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000828

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000487

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.000533 AC: 81 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.000471 AC XY: 35 AN XY: 74342

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000670 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.000889

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

Sep 27, 2021

The c.640G>A (p.V214I) alteration is located in exon 5 (coding exon 5) of the LGR5 gene. This alteration results from a G to A substitution at nucleotide position 640, causing the valine (V) at amino acid position 214 to be replaced by an isoleucine (I). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.81	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.17	T;T
Sift4G	Benign	0.074	T;D
Polyphen		1.0	D;P
Vest4		0.72
MVP		0.97
MPC		0.32
ClinPred		0.11	T
GERP RS		5.9
Varity_R		0.30
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148122019; hg19: chr12-71947064;