19-14151033-A-C

Variant names:

• chr19-14151033-A-C
• NM_014921.5:c.4250T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014921.5(ADGRL1):​c.4250T>G​(p.Ile1417Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: ADGRL1 NM_014921.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23104003).

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.4250T>G	p.Ile1417Ser	missense	Exon 23 of 23	NP_055736.2
	ADGRL1	NM_001008701.3		c.4265T>G	p.Ile1422Ser	missense	Exon 24 of 24	NP_001008701.1	O94910-1
	ADGRL1-AS1	NR_045214.1		n.73-4119A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRL1	ENST00000361434.8	TSL:1 MANE Select	c.4250T>G	p.Ile1417Ser	missense	Exon 23 of 23	ENSP00000355328.2	O94910-2
	ADGRL1	ENST00000340736.10	TSL:1	c.4265T>G	p.Ile1422Ser	missense	Exon 24 of 24	ENSP00000340688.5	O94910-1
	ADGRL1-AS1	ENST00000588387.3	TSL:1	n.80-4119A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.22	T
PhyloP100		3.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.26
Sift	Uncertain	0.018	D
Sift4G	Benign	0.27	T
Polyphen		0.98	D
Vest4		0.28
MutPred		0.60		Gain of glycosylation at I1422 (P = 0.007)
MVP		0.068
MPC		1.0
ClinPred		0.77	D
GERP RS		3.9
Varity_R		0.28
gMVP		0.57
Mutation Taster		=82/18	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

hg19: chr19-14261845;