Genetic Variant ADGRL1:p.Ala1410Pro (chr19-14151055-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014921.5(ADGRL1):c.4228G>C(p.Ala1410Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 0.039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADGRL1
NM_014921.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060198307).

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>C	p.Ala1410Pro	missense	Exon 23 of 23	NP_055736.2
ADGRL1	NM_001008701.3		c.4243G>C	p.Ala1415Pro	missense	Exon 24 of 24	NP_001008701.1	O94910-1
ADGRL1-AS1	NR_045214.1		n.73-4097C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRL1	ENST00000361434.8	TSL:1 MANE Select	c.4228G>C	p.Ala1410Pro	missense	Exon 23 of 23	ENSP00000355328.2	O94910-2
ADGRL1	ENST00000340736.10	TSL:1	c.4243G>C	p.Ala1415Pro	missense	Exon 24 of 24	ENSP00000340688.5	O94910-1
ADGRL1-AS1	ENST00000588387.3	TSL:1	n.80-4097C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0387

AC:

433

AN:

11196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0477

Gnomad AMI

AF:

0.0250

Gnomad AMR

AF:

0.0360

Gnomad ASJ

AF:

0.0241

Gnomad EAS

AF:

0.00896

Gnomad SAS

AF:

0.0268

Gnomad FIN

AF:

0.0395

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0391

Gnomad OTH

AF:

0.0625

GnomAD2 exomes

AF:

0.00921

AC:

198

AN:

21492

AF XY:

0.0107

show subpopulations

Gnomad AFR exome

AF:

0.00100

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.00997

Gnomad EAS exome

AF:

0.00596

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00743

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00284

AC:

651

AN:

228888

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

405

AN XY:

109194

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00393

AC:

AN:

5856

American (AMR)

AF:

0.0262

AC:

AN:

3020

Ashkenazi Jewish (ASJ)

AF:

0.00598

AC:

AN:

2844

East Asian (EAS)

AF:

0.00190

AC:

AN:

3676

South Asian (SAS)

AF:

0.0193

AC:

183

AN:

9492

European-Finnish (FIN)

AF:

0.0175

AC:

120

AN:

6848

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

518

European-Non Finnish (NFE)

AF:

0.00104

AC:

196

AN:

188494

Other (OTH)

AF:

0.00307

AC:

AN:

8140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.302

Heterozygous variant carriers

108

162

216

270

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0386

AC:

433

AN:

11228

Hom.:

Cov.:

AF XY:

0.0346

AC XY:

203

AN XY:

5862

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0473

AC:

130

AN:

2748

American (AMR)

AF:

0.0358

AC:

AN:

1202

Ashkenazi Jewish (ASJ)

AF:

0.0241

AC:

AN:

290

East Asian (EAS)

AF:

0.00903

AC:

AN:

554

South Asian (SAS)

AF:

0.0268

AC:

AN:

410

European-Finnish (FIN)

AF:

0.0395

AC:

AN:

506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0391

AC:

207

AN:

5296

Other (OTH)

AF:

0.0600

AC:

AN:

150

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.282

Heterozygous variant carriers

100

134

167

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:

0.00570

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.95

PhyloP100

1.8

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.42

REVEL

Benign

0.22

Sift

Benign

0.058

Sift4G

Benign

0.33

Polyphen

0.0010

Vest4

0.31

MutPred

0.46

Gain of glycosylation at A1415 (P = 0.0011)

MVP

0.093

MPC

0.45

ClinPred

0.0019

GERP RS

3.9

Varity_R

0.15

gMVP

0.43

Mutation Taster

=92/8

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