chr11-27367901-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_018490.5(LGR4):​c.2822G>A​(p.Arg941His) variant causes a missense change. The variant allele was found at a frequency of 0.0000399 in 1,602,236 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: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

LGR4
NM_018490.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17147318).
BS2
High AC in GnomAd4 at 6 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
LGR4NM_018490.5 linkc.2822G>A p.Arg941His missense_variant Exon 18 of 18 ENST00000379214.9 NP_060960.2 Q9BXB1-1Q59ER8
LGR4NM_001346432.2 linkc.2750G>A p.Arg917His missense_variant Exon 17 of 17 NP_001333361.1 Q9BXB1-2Q59ER8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LGR4ENST00000379214.9 linkc.2822G>A p.Arg941His missense_variant Exon 18 of 18 1 NM_018490.5 ENSP00000368516.4 Q9BXB1-1
LGR4ENST00000389858.4 linkc.2750G>A p.Arg917His missense_variant Exon 17 of 17 1 ENSP00000374508.4 Q9BXB1-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000251
AC:
6
AN:
239348
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
129278
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000315
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000455
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000400
AC:
58
AN:
1450102
Hom.:
0
Cov.:
31
AF XY:
0.0000305
AC XY:
22
AN XY:
721132
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000241
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000460
Gnomad4 OTH exome
AF:
0.0000837
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74328
show subpopulations
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:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000968
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2822G>A (p.R941H) alteration is located in exon 18 (coding exon 18) of the LGR4 gene. This alteration results from a G to A substitution at nucleotide position 2822, causing the arginine (R) at amino acid position 941 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
0.12
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.071
T;.
Eigen
Benign
0.015
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
0.66
N;N
REVEL
Benign
0.077
Sift
Benign
0.21
T;T
Sift4G
Benign
0.52
T;T
Polyphen
0.038
B;.
Vest4
0.10
MVP
0.37
MPC
0.28
ClinPred
0.067
T
GERP RS
5.9
Varity_R
0.071
gMVP
0.097

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.

Other links and lift over

dbSNP: rs202048946; hg19: chr11-27389448; API