11-27472250-G-A

Position:

• chr11-27472250-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_018490.5(LGR4):​c.53C>T​(p.Ser18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,166,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: LGR4 NM_018490.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.486

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-AS1 (HGNC:40629): (LGR4 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21122175).
• BS2: High AC in GnomAdExome4 at 8 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/exons	MANE	Protein	UniProt
LGR4	NM_018490.5	c.53C>T	p.Ser18Leu	missense_variant	1/18	ENST00000379214.9	NP_060960.2
LGR4-AS1	NR_131170.1	n.102+418G>A		intron_variant, non_coding_transcript_variant
LGR4	NM_001346432.2	c.53C>T	p.Ser18Leu	missense_variant	1/17		NP_001333361.1
LGR4-AS1	NR_131169.1	n.102+418G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGR4	ENST00000379214.9	c.53C>T	p.Ser18Leu	missense_variant	1/18	1	NM_018490.5	ENSP00000368516	P1
LGR4-AS1	ENST00000529258.1	n.35+418G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000686 AC: 8 AN: 1166982 Hom.: 0 Cov.: 35 AF XY: 0.0000105 AC XY: 6 AN XY: 569150

Gnomad4 AFR exome AF: 0.000218

Gnomad4 AMR exome AF: 0.000102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000206

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2022

The c.53C>T (p.S18L) alteration is located in exon 1 (coding exon 1) of the LGR4 gene. This alteration results from a C to T substitution at nucleotide position 53, causing the serine (S) at amino acid position 18 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.10	T;T;D
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.13
MutPred		0.25		Loss of glycosylation at S18 (P = 0.0116);Loss of glycosylation at S18 (P = 0.0116);Loss of glycosylation at S18 (P = 0.0116);
MVP		0.37
MPC		0.20
ClinPred		0.13	T
GERP RS		2.0
Varity_R		0.12
gMVP		0.26

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

Other links and lift over

dbSNP: rs1462232131; hg19: chr11-27493797;