chr19-14151055-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_014921.5(ADGRL1):c.4228G>A(p.Ala1410Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1410V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

ADGRL1
NM_014921.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Publications

3 publications found

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08075279).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000671 (8/11916) while in subpopulation AFR AF = 0.0017 (5/2946). AF 95% confidence interval is 0.000669. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014921.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRL1	NM_014921.5	MANE Select	c.4228G>A	p.Ala1410Thr	missense	Exon 23 of 23	NP_055736.2
ADGRL1	NM_001008701.3		c.4243G>A	p.Ala1415Thr	missense	Exon 24 of 24	NP_001008701.1	O94910-1
ADGRL1-AS1	NR_045214.1		n.73-4097C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRL1	ENST00000361434.8	TSL:1 MANE Select	c.4228G>A	p.Ala1410Thr	missense	Exon 23 of 23	ENSP00000355328.2	O94910-2
ADGRL1	ENST00000340736.10	TSL:1	c.4243G>A	p.Ala1415Thr	missense	Exon 24 of 24	ENSP00000340688.5	O94910-1
ADGRL1-AS1	ENST00000588387.3	TSL:1	n.80-4097C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000589

AC:

AN:

11882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00137

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:

0.000539

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000931

AC:

AN:

21492

AF XY:

0.000173

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000340

AC:

AN:

235254

Hom.:

Cov.:

AF XY:

0.0000623

AC XY:

AN XY:

112436

show subpopulations

African (AFR)

AF:

0.000165

AC:

AN:

6058

American (AMR)

AF:

0.00

AC:

AN:

3212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3072

East Asian (EAS)

AF:

0.00

AC:

AN:

4174

South Asian (SAS)

AF:

0.000101

AC:

AN:

9942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

532

European-Non Finnish (NFE)

AF:

0.0000208

AC:

AN:

192594

Other (OTH)

AF:

0.000233

AC:

AN:

8568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000671

AC:

AN:

11916

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

6202

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

2946

American (AMR)

AF:

0.00

AC:

AN:

1340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

296

East Asian (EAS)

AF:

0.00

AC:

AN:

564

South Asian (SAS)

AF:

0.00

AC:

AN:

436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000539

AC:

AN:

5568

Other (OTH)

AF:

0.00

AC:

AN:

162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.87

PhyloP100

1.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.71

REVEL

Benign

0.17

Sift

Benign

0.076

Sift4G

Benign

0.41

Polyphen

0.67

Vest4

0.22

MutPred

0.45

Gain of phosphorylation at A1415 (P = 3e-04)

MVP

0.15

MPC

0.46

ClinPred

0.059

GERP RS

3.9

Varity_R

0.064

gMVP

0.36

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over