8-26770511-A-G

Variant names:

• chr8-26770511-A-G
• rs1048101
• NM_000680.4:c.1039T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000680.4(ADRA1A):​c.1039T>C​(p.Cys347Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,613,560 control chromosomes in the GnomAD database, including 197,390 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.56 (25407 hom., cov: 32)
  • Exomes 𝑓: 0.48 (171983 hom.)
• Consequence: ADRA1A NM_000680.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1556981E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRA1A	NM_000680.4	c.1039T>C	p.Cys347Arg	missense_variant	Exon 3 of 3	ENST00000380573.4	NP_000671.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRA1A	ENST00000380573.4	c.1039T>C	p.Cys347Arg	missense_variant	Exon 3 of 3	2	NM_000680.4	ENSP00000369947.3

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84681 AN: 151896 Hom.: 25383 Cov.: 32

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.895

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.550

GnomAD3 exomes AF: 0.516 AC: 129746 AN: 251386 Hom.: 36044 AF XY: 0.509 AC XY: 69219 AN XY: 135866

Gnomad AFR exome AF: 0.762

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.913

Gnomad SAS exome AF: 0.544

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.490

GnomAD4 exome AF: 0.476 AC: 695250 AN: 1461546 Hom.: 171983 Cov.: 57 AF XY: 0.477 AC XY: 346766 AN XY: 727078

Gnomad4 AFR exome AF: 0.767

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.888

Gnomad4 SAS exome AF: 0.544

Gnomad4 FIN exome AF: 0.373

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.558 AC: 84753 AN: 152014 Hom.: 25407 Cov.: 32 AF XY: 0.555 AC XY: 41246 AN XY: 74292

Gnomad4 AFR AF: 0.755

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.895

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.549

Alfa AF: 0.482 Hom.: 44339

Bravo AF: 0.577

TwinsUK AF: 0.447 AC: 1656

ALSPAC AF: 0.450 AC: 1736

ESP6500AA AF: 0.739 AC: 3258

ESP6500EA AF: 0.445 AC: 3831

ExAC AF: 0.519 AC: 62997

EpiCase AF: 0.462

EpiControl AF: 0.455

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.026	.;.;.;.;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.062	T;T;T;T;.;T
MetaRNN	Benign	0.0000012	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.7	N;N;.;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.7	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.91	T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T
Polyphen		0.0	.;B;.;B;B;B
Vest4		0.068
MPC		0.52
ClinPred		0.0062	T
GERP RS		5.8
Varity_R		0.19
gMVP		0.41

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: rs1048101; hg19: chr8-26628028; COSMIC: COSV52365447; COSMIC: COSV52365447;