Genetic Variant ADGRL3:p.Pro1457Leu (chr4-62070646-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001387552.1(ADGRL3):c.4370C>T(p.Pro1457Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,551,338 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 (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ADGRL3
NM_001387552.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.76

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]

ADGRL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRL3	NM_001387552.1 link	c.4370C>T	p.Pro1457Leu	missense_variant	Exon 27 of 27	ENST00000683033.1	NP_001374481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRL3	ENST00000683033.1 link	c.4370C>T	p.Pro1457Leu	missense_variant	Exon 27 of 27		NM_001387552.1	ENSP00000507980.1		A0A804HKL8

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000129

AC:

AN:

155342

Hom.:

AF XY:

0.0000121

AC XY:

AN XY:

82470

show subpopulations

Gnomad AFR exome

AF:

0.000257

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000143

AC:

AN:

1399398

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

690200

show subpopulations

Gnomad4 AFR exome

AF:

0.000380

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:

0.00000649

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151940

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4148C>T (p.P1383L) alteration is located in exon 23 (coding exon 23) of the ADGRL3 gene. This alteration results from a C to T substitution at nucleotide position 4148, causing the proline (P) at amino acid position 1383 to be replaced by a leucine (L). 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

0.12

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

.;T;T;T;T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D

MetaSVM

Uncertain

0.34

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.6

D;D;D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Vest4

0.69

MVP

0.66

MPC

1.0

ClinPred

0.93

GERP RS

5.4

gMVP

0.56

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over