chr11-27368134-C-T

Variant names:

• chr11-27368134-C-T
• rs72887882
• NM_018490.5:c.2589G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6 BP7 BS1 BS2_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
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.86
• Publications: 2 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 Unknown geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.2589G>A	p.Ser863Ser	synonymous	Exon 18 of 18	NP_060960.2	Q9BXB1-1
	LGR4	NM_001346432.2		c.2517G>A	p.Ser839Ser	synonymous	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.2589G>A	p.Ser863Ser	synonymous	Exon 18 of 18	ENSP00000368516.4	Q9BXB1-1
	LGR4	ENST00000389858.4	TSL:1	c.2517G>A	p.Ser839Ser	synonymous	Exon 17 of 17	ENSP00000374508.4	Q9BXB1-2
	LGR4	ENST00000937760.1		c.2520G>A	p.Ser840Ser	synonymous	Exon 17 of 17	ENSP00000607819.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1649 AN: 151970 Hom.: 13 Cov.: 33

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

GnomAD2 exomes AF: 0.0123 AC: 3085 AN: 251322 AF XY: 0.0128

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 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.: 38 AF XY: 0.0146 AC XY: 10581 AN XY: 727072

African (AFR) AF: 0.00260 AC: 87 AN: 33466

American (AMR) AF: 0.00561 AC: 251 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 128 AN: 26114

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39678

South Asian (SAS) AF: 0.00928 AC: 800 AN: 86252

European-Finnish (FIN) AF: 0.0238 AC: 1270 AN: 53344

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5764

European-Non Finnish (NFE) AF: 0.0163 AC: 18098 AN: 1111854

Other (OTH) AF: 0.0126 AC: 760 AN: 60364

GnomAD4 genome AF: 0.0108 AC: 1650 AN: 152090 Hom.: 13 Cov.: 33 AF XY: 0.0108 AC XY: 801 AN XY: 74354

African (AFR) AF: 0.00258 AC: 107 AN: 41526

American (AMR) AF: 0.00609 AC: 93 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4792

European-Finnish (FIN) AF: 0.0259 AC: 274 AN: 10568

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1087 AN: 67984

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0138 Hom.: 26

Bravo AF: 0.00943

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0140

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	LGR4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.32
DANN	Benign	0.79
PhyloP100		-3.9
Mutation Taster		=100/0	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: rs72887882; hg19: chr11-27389681;