NM_018490.5:c.2575G>C

Variant names:

• chr11-27368148-C-G
• rs765685987
• NM_018490.5:c.2575G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018490.5(LGR4):​c.2575G>C​(p.Asp859His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D859N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LGR4 NM_018490.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90
• Publications: 0 publications found

Genes affected

LGR4 (HGNC:13299): (leucine rich repeat containing G protein-coupled receptor 4) The protein encoded by this gene is a G-protein coupled receptor that binds R-spondins and activates the Wnt signaling pathway. This Wnt signaling pathway activation is necessary for proper development of many organs of the body. [provided by RefSeq, Oct 2016]

LGR4 Gene-Disease associations (from GenCC):

• delayed puberty, self-limited

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39532602).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018490.5. 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
	LGR4	NM_018490.5	MANE Select	c.2575G>C	p.Asp859His	missense	Exon 18 of 18	NP_060960.2	Q9BXB1-1
	LGR4	NM_001346432.2		c.2503G>C	p.Asp835His	missense	Exon 17 of 17	NP_001333361.1	Q9BXB1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGR4	ENST00000379214.9	TSL:1 MANE Select	c.2575G>C	p.Asp859His	missense	Exon 18 of 18	ENSP00000368516.4	Q9BXB1-1
	LGR4	ENST00000389858.4	TSL:1	c.2503G>C	p.Asp835His	missense	Exon 17 of 17	ENSP00000374508.4	Q9BXB1-2
	LGR4	ENST00000937760.1		c.2506G>C	p.Asp836His	missense	Exon 17 of 17	ENSP00000607819.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0049	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.40		Gain of loop (P = 0.0435)
MVP		0.39
MPC		0.86
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.56
Mutation Taster		=27/73	disease causing

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: rs765685987; hg19: chr11-27389695;