chr8-26770462-G-C

Position:

• chr8-26770462-G-C

Variant summary

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

The NM_000680.4(ADRA1A):​c.1088C>G​(p.Pro363Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ADRA1A NM_000680.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

Genes affected

ADRA1A (HGNC:277): (adrenoceptor alpha 1A) Alpha-1-adrenergic receptors (alpha-1-ARs) are members of the G protein-coupled receptor superfamily. They activate mitogenic responses and regulate growth and proliferation of many cells. There are 3 alpha-1-AR subtypes: alpha-1A, -1B and -1D, all of which signal through the Gq/11 family of G-proteins and different subtypes show different patterns of activation. This gene encodes alpha-1A-adrenergic receptor. Alternative splicing of this gene generates four transcript variants, which encode four different isoforms with distinct C-termini but having similar ligand binding properties. [provided by RefSeq, Jul 2008]

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=0.15786478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRA1A	NM_000680.4	c.1088C>G	p.Pro363Arg	missense_variant	3/3	ENST00000380573.4	NP_000671.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADRA1A	ENST00000380573.4	c.1088C>G	p.Pro363Arg	missense_variant	3/3	2	NM_000680.4	ENSP00000369947	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

May 09, 2023

The c.1088C>G (p.P363R) alteration is located in exon 2 (coding exon 2) of the ADRA1A gene. This alteration results from a C to G substitution at nucleotide position 1088, causing the proline (P) at amino acid position 363 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	0.095
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.049	.;.;.;.;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D;D;.;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.0	L;L;.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.30	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.15	T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T
Polyphen		0.98, 0.20, 0.018	.;D;.;B;B;B
Vest4		0.17
MutPred		0.24		Loss of glycosylation at P363 (P = 0.0455);Loss of glycosylation at P363 (P = 0.0455);Loss of glycosylation at P363 (P = 0.0455);Loss of glycosylation at P363 (P = 0.0455);Loss of glycosylation at P363 (P = 0.0455);Loss of glycosylation at P363 (P = 0.0455);
MVP		0.81
MPC		0.75
ClinPred		0.25	T
GERP RS		5.1
Varity_R		0.077
gMVP		0.26

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: rs1438457309; hg19: chr8-26627979;