chr8-37828943-G-A

Position:

• chr8-37828943-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032777.10(ADGRA2):​c.394G>A​(p.Gly132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADGRA2 NM_032777.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

ADGRA2 (HGNC:17849): (adhesion G protein-coupled receptor A2) Predicted to enable G protein-coupled receptor activity. Involved in positive regulation of canonical Wnt signaling pathway. Part of Wnt signalosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2750353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA2	NM_032777.10	c.394G>A	p.Gly132Arg	missense_variant	3/19	ENST00000412232.3	NP_116166.9
ADGRA2	XM_011544481.3	c.394G>A	p.Gly132Arg	missense_variant	3/19		XP_011542783.1
ADGRA2	XM_011544482.3	c.322G>A	p.Gly108Arg	missense_variant	2/18		XP_011542784.1
ADGRA2	XM_011544483.3	c.394G>A	p.Gly132Arg	missense_variant	3/18		XP_011542785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA2	ENST00000412232.3	c.394G>A	p.Gly132Arg	missense_variant	3/19	1	NM_032777.10	ENSP00000406367.2
ADGRA2	ENST00000315215.11	c.394G>A	p.Gly132Arg	missense_variant	3/16	1		ENSP00000323508.7
ADGRA2	ENST00000428068.5	c.268G>A	p.Gly90Arg	missense_variant	3/6	3		ENSP00000400860.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429256 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708594

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

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

Oct 08, 2024

The c.394G>A (p.G132R) alteration is located in exon 3 (coding exon 3) of the ADGRA2 gene. This alteration results from a G to A substitution at nucleotide position 394, causing the glycine (G) at amino acid position 132 to be replaced by an arginine (R). 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	Benign	0.094
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;.;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T;T;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.7	D;N;N
REVEL	Benign	0.088
Sift	Benign	0.17	T;D;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.14, 0.99	.;B;D
Vest4		0.54, 0.52
MutPred		0.41		.;Loss of ubiquitination at K135 (P = 0.0524);Loss of ubiquitination at K135 (P = 0.0524);
MVP		0.45
MPC		0.69
ClinPred		0.76	D
GERP RS		5.8
Varity_R		0.083
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs1168187548; hg19: chr8-37686461;