1-81943464-T-A

Position:

• chr1-81943464-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001366006.2(ADGRL2):​c.905T>A​(p.Phe302Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADGRL2 NM_001366006.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

Genes affected

ADGRL2 (HGNC:18582): (adhesion G protein-coupled receptor L2) This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors. The encoded protein participates in the regulation of exocytosis. The proprotein is thought to be further cleaved within a cysteine-rich G-protein-coupled receptor proteolysis site into two chains that are non-covalently bound at the cell membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL2	NM_001366006.2	c.905T>A	p.Phe302Tyr	missense_variant	6/24	ENST00000686636.1	NP_001352935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL2	ENST00000686636.1	c.905T>A	p.Phe302Tyr	missense_variant	6/24		NM_001366006.2	ENSP00000509478.1
ADGRL2	ENST00000370725.5	c.893T>A	p.Phe298Tyr	missense_variant	8/26	5		ENSP00000359760.1
ADGRL2	ENST00000370723.5	c.893T>A	p.Phe298Tyr	missense_variant	8/25	5		ENSP00000359758.1
ADGRL2	ENST00000370728.5	c.893T>A	p.Phe298Tyr	missense_variant	8/25	5		ENSP00000359763.1
ADGRL2	ENST00000370727.5	c.893T>A	p.Phe298Tyr	missense_variant	8/25	5		ENSP00000359762.1
ADGRL2	ENST00000370730.5	c.893T>A	p.Phe298Tyr	missense_variant	8/24	5		ENSP00000359765.1
ADGRL2	ENST00000370721.5	c.905T>A	p.Phe302Tyr	missense_variant	9/25	5		ENSP00000359756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.893T>A (p.F298Y) alteration is located in exon 5 (coding exon 4) of the ADGRL2 gene. This alteration results from a T to A substitution at nucleotide position 893, causing the phenylalanine (F) at amino acid position 298 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D;.;.;D;.;.;.;.;.;D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;.;D;D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;.;N
REVEL	Pathogenic	0.78
Sift	Benign	0.26	T;D;D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;D;D;D;D;.;.
Vest4		0.65
MutPred		0.58		.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.45
MPC		1.9
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.49
gMVP		0.51

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-82409148;