19-14151199-C-G

Position:

chr19-14151199-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_014921.5(ADGRL1):c.4084G>C(p.Glu1362Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,611,204 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ADGRL1
NM_014921.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.41

Variant links:

Genes affected

ADGRL1 (HGNC:20973): (adhesion G protein-coupled receptor L1) 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. Latrophilin-1 has been shown to recruit the neurotoxin from black widow spider venom, alpha-latrotoxin, to the synapse plasma membrane. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Oct 2008]

ADGRL1 links:

ADGRL1-AS1 (HGNC:55309): (ADGRL1 antisense RNA 1)

ADGRL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADGRL1. . Gene score misZ 3.4265 (greater than the threshold 3.09). Trascript score misZ 4.0179 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay, behavioral abnormalities, and neuropsychiatric disorders.

BP4

Computational evidence support a benign effect (MetaRNN=0.005404651).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL1	NM_014921.5 linkuse as main transcript	c.4084G>C	p.Glu1362Gln	missense_variant	23/23	ENST00000361434.8	NP_055736.2
ADGRL1-AS1	NR_045214.1 linkuse as main transcript	n.73-3953C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL1	ENST00000361434.8 linkuse as main transcript	c.4084G>C	p.Glu1362Gln	missense_variant	23/23	1	NM_014921.5	ENSP00000355328	A1	O94910-2
ADGRL1-AS1	ENST00000588387.2 linkuse as main transcript	n.79-3953C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00432

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:

0.000478

GnomAD3 exomes

AF:

0.000264

AC:

AN:

234676

Hom.:

AF XY:

0.000247

AC XY:

AN XY:

129482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00583

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000391

Gnomad OTH exome

AF:

0.000348

GnomAD4 exome

AF:

0.000126

AC:

184

AN:

1459024

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

725790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00533

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000118

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000653

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.000150

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.4099G>C (p.E1367Q) alteration is located in exon 24 (coding exon 23) of the ADGRL1 gene. This alteration results from a G to C substitution at nucleotide position 4099, causing the glutamic acid (E) at amino acid position 1367 to be replaced by a glutamine (Q). 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.074

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

0.87

N;N

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.78

N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.35

B;B

Vest4

0.079

MVP

0.082

MPC

0.67

ClinPred

0.051

GERP RS

4.2

Varity_R

0.066

gMVP

0.41

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