chr19-14160139-GC-TA

Variant names:

• chr19-14160139-GC-TA
• NM_014921.5:c.1772_1773delGCinsTA
• ADGRL1 p.Arg591Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_014921.5(ADGRL1):c.1772_1773delGCinsTA (p.Arg591Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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)
• 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): ()

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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.1772_1773delGCinsTA p.Arg591Leu	missense	N/A	Prot: NP_055736.2
	ADGRL1 NM_001008701.3		c.1787_1788delGCinsTA p.Arg596Leu	missense	N/A	Prot: NP_001008701.1 UniProt:
	ADGRL1-AS1 NR_045214.1		n.400+4660_400+4661delGCinsTA	intron	Intron 2 of 2	Prot:

ADGRL1 NM_014921.5

MANE Select

HGVSc / HGVSpc.1772_1773delGCinsTAp.Arg591Leu

Exon rankN/A

missense

Prot: NP_055736.2

ADGRL1 NM_001008701.3

HGVSc / HGVSpc.1787_1788delGCinsTAp.Arg596Leu

Exon rankN/A

missense

Prot: NP_001008701.1UniProt: O94910-1

ADGRL1-AS1 NR_045214.1

HGVSc / HGVSpn.400+4660_400+4661delGCinsTA

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.1772_1773delGCinsTA p.Arg591Leu	missense	N/A	Prot: ENSP00000355328.2 UniProt:
	ADGRL1 ENST00000340736.10	TSL:1	c.1787_1788delGCinsTA p.Arg596Leu	missense	N/A	Prot: ENSP00000340688.5 UniProt:
	ADGRL1-AS1 ENST00000588387.3	TSL:1	n.407+4660_407+4661delGCinsTA	intron	Intron 2 of 2	Prot:

ADGRL1 ENST00000361434.8

TSL:1MANE Select

HGVSc / HGVSpc.1772_1773delGCinsTAp.Arg591Leu

Exon rankN/A

missense

Prot: ENSP00000355328.2UniProt: O94910-2

ADGRL1 ENST00000340736.10

TSL:1

HGVSc / HGVSpc.1787_1788delGCinsTAp.Arg596Leu

Exon rankN/A

missense

Prot: ENSP00000340688.5UniProt: O94910-1

ADGRL1-AS1 ENST00000588387.3

TSL:1

HGVSc / HGVSpn.407+4660_407+4661delGCinsTA

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.5

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr19-14270951;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar