10-133128520-G-A

Position:

• chr10-133128520-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083909.3(ADGRA1):​c.692G>A​(p.Arg231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000753 in 1,394,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: ADGRA1 NM_001083909.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0610

Genes affected

ADGRA1 (HGNC:13838): (adhesion G protein-coupled receptor A1) This gene encodes a protein that belongs to the adhesion family of G-protein-coupled receptors. Members of this family function in several sensory systems and regulate blood pressure, immune responses, food intake and development. A similar protein in rodents is thought to play a role in in the regulation of neuronal signaling pathways. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11170015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRA1	NM_001083909.3	c.692G>A	p.Arg231Gln	missense_variant	7/7	ENST00000392607.8
ADGRA1	NM_001291085.2	c.401G>A	p.Arg134Gln	missense_variant	4/4
ADGRA1	XM_011540273.1	c.185G>A	p.Arg62Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRA1	ENST00000392607.8	c.692G>A	p.Arg231Gln	missense_variant	7/7	5	NM_001083909.3	P1
ADGRA1	ENST00000392606.2	c.401G>A	p.Arg134Gln	missense_variant	4/4	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000753 AC: 105 AN: 1394806 Hom.: 0 Cov.: 30 AF XY: 0.0000698 AC XY: 48 AN XY: 687992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000955

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000574 Hom.: 0

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

Jul 25, 2023

The c.692G>A (p.R231Q) alteration is located in exon 7 (coding exon 6) of the ADGRA1 gene. This alteration results from a G to A substitution at nucleotide position 692, causing the arginine (R) at amino acid position 231 to be replaced by a glutamine (Q). 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	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.2
DANN	Benign	0.69
DEOGEN2	Benign	0.035	.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	.;N;.
REVEL	Benign	0.048
Sift	Benign	0.59	.;T;.
Sift4G	Benign	0.071	T;T;T
Polyphen		0.94	P;P;.
Vest4		0.076
MutPred		0.40		.;Loss of sheet (P = 0.0457);.;
MVP		0.13
MPC		0.48
ClinPred		0.14	T
GERP RS		-0.28
Varity_R		0.080
gMVP		0.20

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: rs960359661; hg19: chr10-134942024;