12-71556630-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003667.4(LGR5):ā€‹c.656A>Cā€‹(p.Asn219Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

LGR5
NM_003667.4 missense

Scores

7
5
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.02
Variant links:
Genes affected
LGR5 (HGNC:4504): (leucine rich repeat containing G protein-coupled receptor 5) The protein encoded by this gene is a leucine-rich repeat-containing receptor (LGR) and member of the G protein-coupled, 7-transmembrane receptor (GPCR) superfamily. The encoded protein is a receptor for R-spondins and is involved in the canonical Wnt signaling pathway. This protein plays a role in the formation and maintenance of adult intestinal stem cells during postembryonic development. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LGR5NM_003667.4 linkuse as main transcriptc.656A>C p.Asn219Thr missense_variant 6/18 ENST00000266674.10 NP_003658.1
LOC105369833XR_001749200.2 linkuse as main transcriptn.118+15003T>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LGR5ENST00000266674.10 linkuse as main transcriptc.656A>C p.Asn219Thr missense_variant 6/181 NM_003667.4 ENSP00000266674 P1O75473-1
LGR5ENST00000540815.2 linkuse as main transcriptc.656A>C p.Asn219Thr missense_variant 6/171 ENSP00000441035 O75473-2
LGR5ENST00000536515.5 linkuse as main transcriptc.440A>C p.Asn147Thr missense_variant 5/171 ENSP00000443033 O75473-3
LGR5ENST00000550851.5 linkuse as main transcriptn.753A>C non_coding_transcript_exon_variant 6/202

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457326
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
725326
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 09, 2023The c.656A>C (p.N219T) alteration is located in exon 6 (coding exon 6) of the LGR5 gene. This alteration results from a A to C substitution at nucleotide position 656, causing the asparagine (N) at amino acid position 219 to be replaced by a threonine (T). 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
Pathogenic
0.85
BayesDel_addAF
Benign
0.0092
T
BayesDel_noAF
Benign
-0.22
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Benign
0.050
D
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
1.8
L;.;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.0
D;D;D
REVEL
Uncertain
0.40
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.89
MutPred
0.39
Gain of catalytic residue at R221 (P = 0);.;Gain of catalytic residue at R221 (P = 0);
MVP
0.94
MPC
0.35
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.88
gMVP
0.41

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: rs1877780526; hg19: chr12-71950410; API