NM_001387552.1:c.4315G>A

Variant names:

• chr4-62070591-G-A
• rs780038482
• NM_001387552.1:c.4315G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001387552.1(ADGRL3):​c.4315G>A​(p.Glu1439Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,550,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: ADGRL3 NM_001387552.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.35
• Publications: 0 publications found

Genes affected

ADGRL3 (HGNC:20974): (adhesion G protein-coupled receptor L3) 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. [provided by RefSeq, Jul 2008]

ADGRL3-AS1 (HGNC:50604): (ADGRL3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32280898).
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387552.1. 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
	ADGRL3	NM_001387552.1	MANE Select	c.4315G>A	p.Glu1439Lys	missense	Exon 27 of 27	NP_001374481.1	A0A804HKL8
	ADGRL3	NM_001322402.3		c.4297G>A	p.Glu1433Lys	missense	Exon 26 of 26	NP_001309331.1
	ADGRL3	NM_001371344.2		c.4270G>A	p.Glu1424Lys	missense	Exon 24 of 24	NP_001358273.1	E7EVD6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRL3	ENST00000683033.1	MANE Select	c.4315G>A	p.Glu1439Lys	missense	Exon 27 of 27	ENSP00000507980.1	A0A804HKL8
	ADGRL3	ENST00000512091.6	TSL:1	c.*422G>A		3_prime_UTR	Exon 26 of 26	ENSP00000423388.1	Q9HAR2-2
	ADGRL3	ENST00000506720.5	TSL:5	c.4426G>A	p.Glu1476Lys	missense	Exon 25 of 25	ENSP00000420931.1	E7EUW2

Frequencies

GnomAD3 genomes AF: 0.0000598 AC: 9 AN: 150468 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000604

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

GnomAD2 exomes AF: 0.0000513 AC: 8 AN: 155864 AF XY: 0.0000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000336

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000457 AC: 64 AN: 1399768 Hom.: 0 Cov.: 32 AF XY: 0.0000435 AC XY: 30 AN XY: 690372

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.000392 AC: 14 AN: 35710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000371 AC: 40 AN: 1079046

Other (OTH) AF: 0.0000860 AC: 5 AN: 58118

GnomAD4 genome AF: 0.0000598 AC: 9 AN: 150468 Hom.: 1 Cov.: 32 AF XY: 0.0000546 AC XY: 4 AN XY: 73278

African (AFR) AF: 0.00 AC: 0 AN: 40840

American (AMR) AF: 0.000604 AC: 9 AN: 14896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67920

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.0000344 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.72	T
PhyloP100		9.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.020	D
Sift4G	Benign	0.15	T
Vest4		0.51
MutPred		0.54		Gain of ubiquitination at E1365 (P = 0.001)
MVP		0.43
MPC		0.94
ClinPred		0.27	T
GERP RS		5.6
gMVP		0.50
Mutation Taster		=33/67	disease causing

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: rs780038482; hg19: chr4-62936309;