11-27368556-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBS2_Supporting

The NM_018490.5(LGR4):​c.2167G>A​(p.Val723Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. V723V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

LGR4
NM_018490.5 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.141
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.042518824).
BP6
Variant 11-27368556-C-T is Benign according to our data. Variant chr11-27368556-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3290559.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 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 rank MANE Protein UniProt
LGR4NM_018490.5 linkc.2167G>A p.Val723Ile missense_variant Exon 18 of 18 ENST00000379214.9 NP_060960.2 Q9BXB1-1Q59ER8
LGR4NM_001346432.2 linkc.2095G>A p.Val699Ile 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.2167G>A p.Val723Ile missense_variant Exon 18 of 18 1 NM_018490.5 ENSP00000368516.4 Q9BXB1-1
LGR4ENST00000389858.4 linkc.2095G>A p.Val699Ile missense_variant Exon 17 of 17 1 ENSP00000374508.4 Q9BXB1-2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152050
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000735
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251114
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135738
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000315
AC:
46
AN:
1461272
Hom.:
0
Cov.:
34
AF XY:
0.0000358
AC XY:
26
AN XY:
726978
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152050
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Apr 24, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
7.0
DANN
Benign
0.82
DEOGEN2
Benign
0.096
T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.45
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.043
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.52
N;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.30
N;N
REVEL
Benign
0.088
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0010
B;.
Vest4
0.053
MVP
0.14
MPC
0.18
ClinPred
0.014
T
GERP RS
1.8
Varity_R
0.029
gMVP
0.21

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: rs762481038; hg19: chr11-27390103; API