Genetic Variant ADGRL3:p.Pro1406Ser (chr4-62070492-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001387552.1(ADGRL3):c.4216C>T(p.Pro1406Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000517 in 1,547,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1406A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ADGRL3
NM_001387552.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

Publications

3 publications found

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:

ADGRL3-AS1 (HGNC:50604): (ADGRL3 antisense RNA 1)

ADGRL3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27828473).

BS2

High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387552.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRL3	NM_001387552.1	MANE Select	c.4216C>T	p.Pro1406Ser	missense	Exon 27 of 27	NP_001374481.1	A0A804HKL8
ADGRL3	NM_001322402.3		c.4198C>T	p.Pro1400Ser	missense	Exon 26 of 26	NP_001309331.1
ADGRL3	NM_001371344.2		c.4171C>T	p.Pro1391Ser	missense	Exon 24 of 24	NP_001358273.1	E7EVD6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRL3	ENST00000683033.1	MANE Select	c.4216C>T	p.Pro1406Ser	missense	Exon 27 of 27	ENSP00000507980.1	A0A804HKL8
ADGRL3	ENST00000512091.6	TSL:1	c.*323C>T		3_prime_UTR	Exon 26 of 26	ENSP00000423388.1	Q9HAR2-2
ADGRL3	ENST00000506720.5	TSL:5	c.4327C>T	p.Pro1443Ser	missense	Exon 25 of 25	ENSP00000420931.1	E7EUW2

Frequencies

GnomAD3 genomes

AF:

0.0000540

AC:

AN:

148196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

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:

0.000105

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000324

AC:

AN:

154260

AF XY:

0.0000122

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:

0.0000858

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1399484

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

690236

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31600

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000649

AC:

AN:

1078970

Other (OTH)

AF:

0.0000172

AC:

AN:

58036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.0000540

AC:

AN:

148196

Hom.:

Cov.:

AF XY:

0.0000828

AC XY:

AN XY:

72456

show subpopulations

African (AFR)

AF:

0.0000249

AC:

AN:

40088

American (AMR)

AF:

0.00

AC:

AN:

14928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4970

South Asian (SAS)

AF:

0.00

AC:

AN:

4552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.000105

AC:

AN:

66596

Other (OTH)

AF:

0.00

AC:

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000683

Hom.:

ExAC

AF:

0.0000320

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.038

MetaRNN

Benign

0.28

MetaSVM

Uncertain

-0.19

PhyloP100

5.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.35

Sift

Benign

0.30

Sift4G

Uncertain

0.048

Vest4

0.16

MutPred

0.58

Loss of catalytic residue at P1331 (P = 0.0168)

MVP

0.20

MPC

0.53

ClinPred

0.36

GERP RS

5.5

gMVP

0.46

Mutation Taster

=64/36

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

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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