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GeneBe

4-61587263-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001387552.1(ADGRL3):c.296G>A(p.Arg99His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADGRL3
NM_001387552.1 missense

Scores

5
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.74
Variant links:
Genes affected
ADGRL3 (HGNC:20974): (adhesion G protein-coupled receptor L3) This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS (G-protein-coupled-receptor proteolysis site) domain resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with substantial similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound at the cell membrane. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADGRL3NM_001387552.1 linkuse as main transcriptc.296G>A p.Arg99His missense_variant 5/27 ENST00000683033.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADGRL3ENST00000683033.1 linkuse as main transcriptc.296G>A p.Arg99His missense_variant 5/27 NM_001387552.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1457022
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
724496
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000166
AC:
2

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 GeneticsMay 16, 2023The c.92G>A (p.R31H) alteration is located in exon 2 (coding exon 2) of the ADGRL3 gene. This alteration results from a G to A substitution at nucleotide position 92, causing the arginine (R) at amino acid position 31 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
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
Cadd
Pathogenic
33
Dann
Pathogenic
1.0
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.067
D
MetaRNN
Uncertain
0.71
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.17
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.6
D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.99
D;.;.;.;.;.;D;.;.;.;.;.;.;.
Vest4
0.81
MutPred
0.45
Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);.;.;Gain of sheet (P = 0.0101);.;.;.;Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);.;.;Gain of sheet (P = 0.0101);
MVP
0.62
MPC
1.1
ClinPred
0.98
D
GERP RS
5.0
gMVP
0.63

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: rs764433793; hg19: chr4-62452981; COSMIC: COSV72265444; COSMIC: COSV72265444; API