chr4-62070816-A-T

Variant names:

• chr4-62070816-A-T
• rs1317134909
• NM_001387552.1:c.4540A>T

Variant summary

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

The NM_001387552.1(ADGRL3):​c.4540A>T​(p.Ser1514Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,399,404 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S1514G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADGRL3 NM_001387552.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4540A>T	p.Ser1514Cys	missense	Exon 27 of 27	NP_001374481.1	A0A804HKL8
	ADGRL3	NM_001322402.3		c.4522A>T	p.Ser1508Cys	missense	Exon 26 of 26	NP_001309331.1
	ADGRL3	NM_001371344.2		c.4495A>T	p.Ser1499Cys	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.4540A>T	p.Ser1514Cys	missense	Exon 27 of 27	ENSP00000507980.1	A0A804HKL8
	ADGRL3	ENST00000512091.6	TSL:1	c.*647A>T		3_prime_UTR	Exon 26 of 26	ENSP00000423388.1	Q9HAR2-2
	ADGRL3	ENST00000506720.5	TSL:5	c.4651A>T	p.Ser1551Cys	missense	Exon 25 of 25	ENSP00000420931.1	E7EUW2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399404 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690208

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078948

Other (OTH) AF: 0.00 AC: 0 AN: 58006

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.074	D
PhyloP100		7.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Vest4		0.53
MutPred		0.69		Loss of disorder (P = 0.0071)
MVP		0.19
MPC		0.97
ClinPred		0.96	D
GERP RS		5.5
gMVP		0.67
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: rs1317134909; hg19: chr4-62936534;