rs587777005

chr11-27391119-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_018490.5(LGR4):c.376C>T(p.Arg126Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000186 in 1,609,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LGR4 NM_018490.5 stop_gained
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 3.79

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_018490.5 Downstream stopcodon found after 13 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGR4	NM_018490.5	c.376C>T	p.Arg126Ter	stop_gained	4/18	ENST00000379214.9
LGR4	NM_001346432.2	c.304C>T	p.Arg102Ter	stop_gained	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGR4	ENST00000379214.9	c.376C>T	p.Arg126Ter	stop_gained	4/18	1	NM_018490.5	P1
LGR4	ENST00000389858.4	c.304C>T	p.Arg102Ter	stop_gained	3/17	1
LGR4	ENST00000480977.2	c.258-5651C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457446 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74192

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Bone mineral density quantitative trait locus 17 Other:1

association, no assertion criteria provided

literature only

OMIM

May 23, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.82
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587777005; hg19: chr11-27412666; COSMIC: COSV101003857;