NM_003667.4:c.653A>G

Variant names:

• chr12-71556627-A-G
• rs117535164
• NM_003667.4:c.653A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003667.4(LGR5):​c.653A>G​(p.His218Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,608,868 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H218Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (10 hom.)
• Consequence: LGR5 NM_003667.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.22
• Publications: 7 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014073074).
• BP6: Variant 12-71556627-A-G is Benign according to our data. Variant chr12-71556627-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 715913.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 10 gene

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.653A>G	p.His218Arg	missense	Exon 6 of 18	NP_003658.1	O75473-1
	LGR5	NM_001277226.2		c.653A>G	p.His218Arg	missense	Exon 6 of 17	NP_001264155.1	O75473-2
	LGR5	NM_001277227.2		c.437A>G	p.His146Arg	missense	Exon 5 of 17	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.653A>G	p.His218Arg	missense	Exon 6 of 18	ENSP00000266674.4	O75473-1
	LGR5	ENST00000540815.2	TSL:1	c.653A>G	p.His218Arg	missense	Exon 6 of 17	ENSP00000441035.2	O75473-2
	LGR5	ENST00000536515.5	TSL:1	c.437A>G	p.His146Arg	missense	Exon 5 of 17	ENSP00000443033.1	O75473-3

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00235 AC: 590 AN: 251284 AF XY: 0.00240

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00240 AC: 3490 AN: 1456556 Hom.: 10 Cov.: 28 AF XY: 0.00247 AC XY: 1789 AN XY: 724954

African (AFR) AF: 0.000330 AC: 11 AN: 33362

American (AMR) AF: 0.000514 AC: 23 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 72 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00244 AC: 210 AN: 86144

European-Finnish (FIN) AF: 0.00217 AC: 116 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00266 AC: 2949 AN: 1107210

Other (OTH) AF: 0.00179 AC: 108 AN: 60212

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00209 AC XY: 156 AN XY: 74478

African (AFR) AF: 0.000481 AC: 20 AN: 41566

American (AMR) AF: 0.000457 AC: 7 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00329 AC: 224 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00286 Hom.: 1

Bravo AF: 0.00175

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.092
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
PhyloP100		7.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.19
Sift	Benign	0.046	D
Sift4G	Uncertain	0.058	T
Polyphen		0.12	B
Vest4		0.52
MVP		0.78
MPC		0.063
ClinPred		0.075	T
GERP RS		4.4
Varity_R		0.72
gMVP		0.59
Mutation Taster		=83/17	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: rs117535164; hg19: chr12-71950407; COSMIC: COSV57006578;