Variant 4-62070591-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001387552.1(ADGRL3):c.4315G>A(p.Glu1439Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,550,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

ADGRL3
NM_001387552.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.35

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32280898).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL3	NM_001387552.1 linkuse as main transcript	c.4315G>A	p.Glu1439Lys	missense_variant	27/27	ENST00000683033.1	NP_001374481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL3	ENST00000683033.1 linkuse as main transcript	c.4315G>A	p.Glu1439Lys	missense_variant	27/27		NM_001387552.1	ENSP00000507980

Frequencies

GnomAD3 genomes

AF:

0.0000598

AC:

AN:

150468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000604

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

GnomAD3 exomes

AF:

0.0000513

AC:

AN:

155864

Hom.:

AF XY:

0.0000243

AC XY:

AN XY:

82450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000879

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000336

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000457

AC:

AN:

1399768

Hom.:

Cov.:

AF XY:

0.0000435

AC XY:

AN XY:

690372

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000392

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000371

Gnomad4 OTH exome

AF:

0.0000860

GnomAD4 genome

AF:

0.0000598

AC:

AN:

150468

Hom.:

Cov.:

AF XY:

0.0000546

AC XY:

AN XY:

73278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000604

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.0000344

AC:

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

Mar 25, 2024

The c.4093G>A (p.E1365K) alteration is located in exon 23 (coding exon 23) of the ADGRL3 gene. This alteration results from a G to A substitution at nucleotide position 4093, causing the glutamic acid (E) at amino acid position 1365 to be replaced by a lysine (K). 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

0.027

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

.;T;T;T;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.32

T;T;T;T;T;T

MetaSVM

Benign

-0.72

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.1

N;N;N;N;N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.020

D;D;D;D;D;D

Sift4G

Benign

0.15

T;T;T;T;T;T

Vest4

0.51

MutPred

0.54

Gain of ubiquitination at E1365 (P = 0.001);.;.;.;.;.;

MVP

0.43

MPC

0.94

ClinPred

0.27

GERP RS

5.6

gMVP

0.50

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