chr19-14151054-G-A

Position:

chr19-14151054-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_ModerateBS1BS2

The NM_014921.5(ADGRL1):c.4229C>T(p.Ala1410Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,490,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

ADGRL1
NM_014921.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.757

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:):

ADGRL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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=0.068143725).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00000896 (12/1339278) while in subpopulation AFR AF= 0.0004 (12/29998). AF 95% confidence interval is 0.00023. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 45. This position pass quality control queck.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL1	NM_014921.5 linkuse as main transcript	c.4229C>T	p.Ala1410Val	missense_variant	23/23	ENST00000361434.8	NP_055736.2	O94910-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL1	ENST00000361434.8 linkuse as main transcript	c.4229C>T	p.Ala1410Val	missense_variant	23/23	1	NM_014921.5	ENSP00000355328.2		O94910-2

Frequencies

GnomAD3 genomes

AF:

0.0000597

AC:

AN:

150828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

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:

0.00

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.0000288

AC:

AN:

104176

Hom.:

AF XY:

0.0000183

AC XY:

AN XY:

54766

show subpopulations

Gnomad AFR exome

AF:

0.000468

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:

0.00000896

AC:

AN:

1339278

Hom.:

Cov.:

AF XY:

0.0000107

AC XY:

AN XY:

655182

show subpopulations

Gnomad4 AFR exome

AF:

0.000400

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000597

AC:

AN:

150828

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73636

show subpopulations

Gnomad4 AFR

AF:

0.000195

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:

0.00

Gnomad4 OTH

AF:

0.000484

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

Dec 04, 2024

The c.4244C>T (p.A1415V) alteration is located in exon 24 (coding exon 23) of the ADGRL1 gene. This alteration results from a C to T substitution at nucleotide position 4244, causing the alanine (A) at amino acid position 1415 to be replaced by a valine (V). 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

0.077

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.95

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.085

Sift

Benign

0.23

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.026

B;B

Vest4

0.25

MutPred

0.50

Loss of relative solvent accessibility (P = 0.0981);.;

MVP

0.17

MPC

0.37

ClinPred

0.026

GERP RS

2.9

Varity_R

0.064

gMVP

0.42

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