11-27368148-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

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=0.39532602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGR4	NM_018490.5	c.2575G>C	p.Asp859His	missense_variant	Exon 18 of 18	ENST00000379214.9	NP_060960.2
LGR4	NM_001346432.2	c.2503G>C	p.Asp835His	missense_variant	Exon 17 of 17		NP_001333361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGR4	ENST00000379214.9	c.2575G>C	p.Asp859His	missense_variant	Exon 18 of 18	1	NM_018490.5	ENSP00000368516.4
LGR4	ENST00000389858.4	c.2503G>C	p.Asp835His	missense_variant	Exon 17 of 17	1		ENSP00000374508.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2575G>C (p.D859H) alteration is located in exon 18 (coding exon 18) of the LGR4 gene. This alteration results from a G to C substitution at nucleotide position 2575, causing the aspartic acid (D) at amino acid position 859 to be replaced by a histidine (H). 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	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;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.030	D;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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-27389695;