NM_014921.5:c.4248A>C

Variant names:

• chr19-14151035-T-G
• rs1273547234
• NM_014921.5:c.4248A>C

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.4248A>C​(p.Glu1416Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,255,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1416K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 29)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: ADGRL1 NM_014921.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.600
• 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=0.10820651).

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.4248A>C	p.Glu1416Asp	missense	Exon 23 of 23	NP_055736.2
	ADGRL1	NM_001008701.3		c.4263A>C	p.Glu1421Asp	missense	Exon 24 of 24	NP_001008701.1	O94910-1
	ADGRL1-AS1	NR_045214.1		n.73-4117T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRL1	ENST00000361434.8	TSL:1 MANE Select	c.4248A>C	p.Glu1416Asp	missense	Exon 23 of 23	ENSP00000355328.2	O94910-2
	ADGRL1	ENST00000340736.10	TSL:1	c.4263A>C	p.Glu1421Asp	missense	Exon 24 of 24	ENSP00000340688.5	O94910-1
	ADGRL1-AS1	ENST00000588387.3	TSL:1	n.80-4117T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000712 AC: 1 AN: 140456 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.97e-7 AC: 1 AN: 1115134 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 542818

African (AFR) AF: 0.0000412 AC: 1 AN: 24292

American (AMR) AF: 0.00 AC: 0 AN: 24122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13630

East Asian (EAS) AF: 0.00 AC: 0 AN: 15310

South Asian (SAS) AF: 0.00 AC: 0 AN: 71348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 897150

Other (OTH) AF: 0.00 AC: 0 AN: 40394

GnomAD4 genome AF: 0.00000712 AC: 1 AN: 140456 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 68096

African (AFR) AF: 0.0000256 AC: 1 AN: 39078

American (AMR) AF: 0.00 AC: 0 AN: 14338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3296

East Asian (EAS) AF: 0.00 AC: 0 AN: 4024

South Asian (SAS) AF: 0.00 AC: 0 AN: 3764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64002

Other (OTH) AF: 0.00 AC: 0 AN: 1982

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.80
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.69	T
PhyloP100		0.60
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	1.5	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.017	B
Vest4		0.21
MutPred		0.69		Loss of catalytic residue at E1421 (P = 0.0826)
MVP		0.11
MPC		0.32
ClinPred		0.64	D
GERP RS		3.9
Varity_R		0.093
gMVP		0.34
Mutation Taster		=90/10	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: rs1273547234; hg19: chr19-14261847;