Genetic Variant LGR4:p.Ser863Ser (chr11-27368134-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6BP7BS1BS2_Supporting

The NM_018490.5(LGR4):c.2589G>A(p.Ser863Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,613,640 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.011 ( 13 hom., cov: 33)

Exomes 𝑓: 0.015 ( 203 hom. )

Consequence

LGR4
NM_018490.5 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -3.86

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 11-27368134-C-T is Benign according to our data. Variant chr11-27368134-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3037795.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-3.86 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0108 (1650/152090) while in subpopulation NFE AF= 0.016 (1087/67984). AF 95% confidence interval is 0.0152. There are 13 homozygotes in gnomad4. There are 801 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1650 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGR4	NM_018490.5 link	c.2589G>A	p.Ser863Ser	synonymous_variant	Exon 18 of 18	ENST00000379214.9	NP_060960.2	Q9BXB1-1Q59ER8
LGR4	NM_001346432.2 link	c.2517G>A	p.Ser839Ser	synonymous_variant	Exon 17 of 17		NP_001333361.1	Q9BXB1-2Q59ER8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGR4	ENST00000379214.9 link	c.2589G>A	p.Ser863Ser	synonymous_variant	Exon 18 of 18	1	NM_018490.5	ENSP00000368516.4		Q9BXB1-1
LGR4	ENST00000389858.4 link	c.2517G>A	p.Ser839Ser	synonymous_variant	Exon 17 of 17	1		ENSP00000374508.4		Q9BXB1-2

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1649

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.0259

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.0123

AC:

3085

AN:

251322

Hom.:

AF XY:

0.0128

AC XY:

1743

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00541

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00898

Gnomad FIN exome

AF:

0.0259

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0147

AC:

21481

AN:

1461550

Hom.:

203

Cov.:

AF XY:

0.0146

AC XY:

10581

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.00561

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00928

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.0163

Gnomad4 OTH exome

AF:

0.0126

GnomAD4 genome

AF:

0.0108

AC:

1650

AN:

152090

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

801

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.00609

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.0259

Gnomad4 NFE

AF:

0.0160

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00943

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0140

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

LGR4-related disorder

Benign:1

Jan 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.32

DANN

Benign

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over