NM_000680.4:c.1039T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C347Y) has been classified as Uncertain significance.

• 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
• Publications: 98 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000680.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA1A	NM_000680.4	MANE Select	c.1039T>C	p.Cys347Arg	missense	Exon 3 of 3	NP_000671.2	P35348-1
	ADRA1A	NM_033303.4		c.1039T>C	p.Cys347Arg	missense	Exon 2 of 3	NP_150646.3	B0ZBD3
	ADRA1A	NM_033304.3		c.1039T>C	p.Cys347Arg	missense	Exon 2 of 3	NP_150647.2	P35348-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA1A	ENST00000380573.4	TSL:2 MANE Select	c.1039T>C	p.Cys347Arg	missense	Exon 3 of 3	ENSP00000369947.3	P35348-1
	ADRA1A	ENST00000380586.5	TSL:1	c.1039T>C	p.Cys347Arg	missense	Exon 2 of 3	ENSP00000369960.1	P35348-2
	ADRA1A	ENST00000276393.8	TSL:1	c.1039T>C	p.Cys347Arg	missense	Exon 2 of 2	ENSP00000276393.4	P35348-1

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

GnomAD2 exomes AF: 0.516 AC: 129746 AN: 251386 AF XY: 0.509

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 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

African (AFR) AF: 0.767 AC: 25670 AN: 33480

American (AMR) AF: 0.502 AC: 22438 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12928 AN: 26136

East Asian (EAS) AF: 0.888 AC: 35266 AN: 39700

South Asian (SAS) AF: 0.544 AC: 46959 AN: 86254

European-Finnish (FIN) AF: 0.373 AC: 19903 AN: 53400

Middle Eastern (MID) AF: 0.561 AC: 3235 AN: 5766

European-Non Finnish (NFE) AF: 0.448 AC: 497541 AN: 1111706

Other (OTH) AF: 0.519 AC: 31310 AN: 60384

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

African (AFR) AF: 0.755 AC: 31322 AN: 41466

American (AMR) AF: 0.539 AC: 8229 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1709 AN: 3470

East Asian (EAS) AF: 0.895 AC: 4617 AN: 5160

South Asian (SAS) AF: 0.563 AC: 2706 AN: 4808

European-Finnish (FIN) AF: 0.364 AC: 3844 AN: 10558

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30671 AN: 67956

Other (OTH) AF: 0.549 AC: 1160 AN: 2114

Alfa AF: 0.492 Hom.: 88898

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 v4.9

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
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.062	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.12
Sift	Benign	0.91	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.068
MPC		0.52
ClinPred		0.0062	T
GERP RS		5.8
Varity_R		0.19
gMVP		0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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