4-61587227-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001387552.1(ADGRL3):ā€‹c.260C>Gā€‹(p.Ala87Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000055 in 1,598,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000059 ( 0 hom. )

Consequence

ADGRL3
NM_001387552.1 missense, splice_region

Scores

3
14
Splicing: ADA: 0.001211
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11336231).
BS2
High AC in GnomAdExome4 at 85 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADGRL3NM_001387552.1 linkuse as main transcriptc.260C>G p.Ala87Gly missense_variant, splice_region_variant 5/27 ENST00000683033.1 NP_001374481.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADGRL3ENST00000683033.1 linkuse as main transcriptc.260C>G p.Ala87Gly missense_variant, splice_region_variant 5/27 NM_001387552.1 ENSP00000507980.1 A0A804HKL8

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000569
AC:
13
AN:
228356
Hom.:
0
AF XY:
0.0000568
AC XY:
7
AN XY:
123332
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000341
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:
0.0000197
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000588
AC:
85
AN:
1446806
Hom.:
0
Cov.:
30
AF XY:
0.0000515
AC XY:
37
AN XY:
718450
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000304
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:
0.0000625
Gnomad4 OTH exome
AF:
0.0000502
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152092
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74272
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000332
AC:
4

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 GeneticsMar 20, 2024The c.56C>G (p.A19G) alteration is located in exon 2 (coding exon 2) of the ADGRL3 gene. This alteration results from a C to G substitution at nucleotide position 56, causing the alanine (A) at amino acid position 19 to be replaced by a glycine (G). 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
Benign
-0.24
T
BayesDel_noAF
Benign
-0.29
CADD
Uncertain
24
DANN
Benign
0.26
DEOGEN2
Benign
0.0029
.;.;.;T;T;T;.;T;.;T;T;T;T;T
Eigen
Benign
0.083
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.86
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationTaster
Benign
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
0.60
N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.18
Sift
Benign
1.0
T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.93
T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.76
P;.;.;.;.;.;P;.;.;.;.;.;.;.
Vest4
0.56
MutPred
0.51
Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);.;.;Gain of relative solvent accessibility (P = 0.0082);.;.;.;Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);.;.;Gain of relative solvent accessibility (P = 0.0082);
MVP
0.56
MPC
0.35
ClinPred
0.083
T
GERP RS
5.8
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0012
dbscSNV1_RF
Benign
0.13
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: rs748085548; hg19: chr4-62452945; COSMIC: COSV105941089; COSMIC: COSV105941089; API