8-26770519-T-G

Position:

• chr8-26770519-T-G

Variant summary

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

The NM_000680.4(ADRA1A):​c.1031A>C​(p.Gln344Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADRA1A NM_000680.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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 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
ADRA1A	NM_000680.4	c.1031A>C	p.Gln344Pro	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.1031A>C	p.Gln344Pro	missense_variant	3/3	2	NM_000680.4	ENSP00000369947	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 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

Oct 10, 2023

The c.1031A>C (p.Q344P) alteration is located in exon 2 (coding exon 2) of the ADRA1A gene. This alteration results from a A to C substitution at nucleotide position 1031, causing the glutamine (Q) at amino acid position 344 to be replaced by a proline (P). 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	0.096
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;.;.;.;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;D;T;T;.;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M;M;.;M;M;M
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N;N;D;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.015	D;D;D;D;D;D
Sift4G	Benign	0.16	T;T;T;D;D;D
Polyphen		0.99, 1.0, 0.98	.;D;.;D;D;D
Vest4		0.73
MutPred		0.56		Gain of catalytic residue at Q344 (P = 0.0328);Gain of catalytic residue at Q344 (P = 0.0328);Gain of catalytic residue at Q344 (P = 0.0328);Gain of catalytic residue at Q344 (P = 0.0328);Gain of catalytic residue at Q344 (P = 0.0328);Gain of catalytic residue at Q344 (P = 0.0328);
MVP		0.74
MPC		0.79
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1806064105; hg19: chr8-26628036;