12-71556630-A-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_003667.4(LGR5):āc.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
NM_003667.4 missense
Scores
7
5
7
Clinical Significance
Conservation
PhyloP100: 9.02
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 |
---|---|---|---|---|---|---|---|---|
LGR5 | NM_003667.4 | c.656A>C | p.Asn219Thr | missense_variant | 6/18 | ENST00000266674.10 | NP_003658.1 | |
LOC105369833 | XR_001749200.2 | n.118+15003T>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LGR5 | ENST00000266674.10 | c.656A>C | p.Asn219Thr | missense_variant | 6/18 | 1 | NM_003667.4 | ENSP00000266674 | P1 | |
LGR5 | ENST00000540815.2 | c.656A>C | p.Asn219Thr | missense_variant | 6/17 | 1 | ENSP00000441035 | |||
LGR5 | ENST00000536515.5 | c.440A>C | p.Asn147Thr | missense_variant | 5/17 | 1 | ENSP00000443033 | |||
LGR5 | ENST00000550851.5 | n.753A>C | non_coding_transcript_exon_variant | 6/20 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457326Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1AN XY: 725326
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
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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 submitter | clinical testing | Ambry Genetics | Dec 09, 2023 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Gain of catalytic residue at R221 (P = 0);.;Gain of catalytic residue at R221 (P = 0);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at