19-14160140-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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 frequency of 0.000000696 in 1,436,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R591H) has been classified as Uncertain significance.

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27762234).

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

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

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436918 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 709050

African (AFR) AF: 0.00 AC: 0 AN: 33042

American (AMR) AF: 0.00 AC: 0 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 38896

South Asian (SAS) AF: 0.00 AC: 0 AN: 85646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1092072

Other (OTH) AF: 0.00 AC: 0 AN: 59138

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.094
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.75	P
Vest4		0.55
MutPred		0.45		Loss of MoRF binding (P = 0.0279)
MVP		0.043
MPC		1.4
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.39
gMVP		0.68
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1202804312; hg19: chr19-14270952;