rs1202804312

Variant names:

• chr19-14160140-C-T
• rs1202804312
• NM_014921.5:c.1772G>A
• ADGRL1 p.Arg591His

Your query was ambiguous. Multiple possible variants found:

• chr19-14160140-C-T
• chr19-14160140-C-A

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_Moderate

The NR_045214.1(ADGRL1-AS1):n.400+4661C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: NR_045214.1 is not a MANE Select or MANE Plus Clinical transcript for ADGRL1-AS1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.00000626 (AC=9) in the gnomAD database across 1,436,916 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000159. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: ADGRL1-AS1 NR_045214.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000159 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NR_045214.1. 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>A p.Arg591His	missense	Exon 8 of 23	Prot: NP_055736.2
	ADGRL1 NM_001008701.3		c.1787G>A p.Arg596His	missense	Exon 9 of 24	Prot: NP_001008701.1 UniProt:
	ADGRL1-AS1 NR_045214.1		n.400+4661C>T	intron	Intron 2 of 2	Prot:

ADGRL1 NM_014921.5

MANE Select

HGVSc / HGVSpc.1772G>Ap.Arg591His

Exon rankExon 8 of 23

missense

Prot: NP_055736.2

ADGRL1 NM_001008701.3

HGVSc / HGVSpc.1787G>Ap.Arg596His

Exon rankExon 9 of 24

missense

Prot: NP_001008701.1UniProt: O94910-1

ADGRL1-AS1 NR_045214.1

HGVSc / HGVSpn.400+4661C>T

Exon rankIntron 2 of 2

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ADGRL1 ENST00000361434.8	TSL:1MANE Select	c.1772G>A p.Arg591His	missense	Exon 8 of 23	Prot: ENSP00000355328.2 UniProt:
	ADGRL1 ENST00000340736.10	TSL:1	c.1787G>A p.Arg596His	missense	Exon 9 of 24	Prot: ENSP00000340688.5 UniProt:
	ADGRL1-AS1 ENST00000588387.3	TSL:1	n.407+4661C>T	intron	Intron 2 of 2	Prot:

ADGRL1 ENST00000361434.8

TSL:1MANE Select

HGVSc / HGVSpc.1772G>Ap.Arg591His

Exon rankExon 8 of 23

missense

Prot: ENSP00000355328.2UniProt: O94910-2

ADGRL1 ENST00000340736.10

TSL:1

HGVSc / HGVSpc.1787G>Ap.Arg596His

Exon rankExon 9 of 24

missense

Prot: ENSP00000340688.5UniProt: O94910-1

ADGRL1-AS1 ENST00000588387.3

TSL:1

HGVSc / HGVSpn.407+4661C>T

Exon rankIntron 2 of 2

intron

Prot:

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.0000121	AC:3	Hom:	AN:248230	Cov:
GnomAD4 exome	AF: 0.00000626	AC:9	Hom:0	AN:1436916	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122204	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00000970	1	103110	0.0000109	2	183846

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.54	D
FuncVEP CTI	Pathogenic	0.69
GPN-Star LLR	N/A	-7.6
GPN-Star score	N/A	7.6
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.2	T
Mutation Taster	N/A	87/13	polymorphism
PhyloP100	Benign	2.5
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.033	D
Varity_R	N/A	0.22
VESM-3B	Benign	-8.6

Showing 27 of 27 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1202804312;

hg19: chr19-14270952;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar