19-14160140-C-A

Variant names:

• chr19-14160140-C-A
• rs1202804312
• NM_014921.5:c.1772G>T
• ADGRL1 p.Arg591Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_014921.5(ADGRL1):c.1772G>T (p.Arg591Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000696 (AC=1) in the gnomAD database across 1,436,918 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000916. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R591H: Likely_benign (ClinVar VariationId 520684, 1 star)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADGRL1 NM_014921.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental delay, behavioral abnormalities, and neuropsychiatric disorders

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia

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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 0 points.

• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000916 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRL1	NM_014921.5	MANE Select	c.1772G>T	p.Arg591Leu	missense	Exon 8 of 23	NP_055736.2
	ADGRL1	NM_001008701.3		c.1787G>T	p.Arg596Leu	missense	Exon 9 of 24	NP_001008701.1	O94910-1
	ADGRL1-AS1	NR_045214.1		n.400+4661C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRL1	ENST00000361434.8	TSL:1 MANE Select	c.1772G>T	p.Arg591Leu	missense	Exon 8 of 23	ENSP00000355328.2	O94910-2
	ADGRL1	ENST00000340736.10	TSL:1	c.1787G>T	p.Arg596Leu	missense	Exon 9 of 24	ENSP00000340688.5	O94910-1
	ADGRL1-AS1	ENST00000588387.3	TSL:1	n.407+4661C>A		intron	N/A

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes					33
GnomAD4 exome	6.96e-7	1	0	1436918	32
GnomAD4 genome					33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	28
AlphaMissense	Pathogenic	-	0.83
BayesDel_addAF	Benign	T	-0.15
BayesDel_noAF	Benign	-	-0.45
CADD	Uncertain	-	25
DANN	Uncertain	-	1.0
DEOGEN2	Benign	T	0.20
Eigen	Uncertain	-	0.20
Eigen_PC	Uncertain	-	0.23
FATHMM_MKL	Uncertain	D	0.89
FuncVEP CTI	Pathogenic	-	0.44
GPN-Star LLR	N/A	-	-8.9
GPN-Star score	N/A	-	8.9
LIST_S2	Pathogenic	D	0.98
M_CAP	Benign	T	0.018
MetaRNN	Benign	T	0.28
MetaSVM	Benign	T	-1.1
Mutation Taster	N/A	polymorphism	76/24
PhyloP100	Benign	-	2.5
popEVE	Benign	-	-3.1
PrimateAI	Uncertain	T	0.70
PROVEAN	Uncertain	D	-3.7
REVEL	Benign	-	0.094
Sift	Uncertain	D	0.0050
Sift4G	Uncertain	D	0.012
Varity_R	N/A	-	0.39
VESM-3B	Benign	-	-8.7

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1202804312;

hg19: chr19-14270952;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar