Genetic Variant ADRA1B:p.Pro325Thr (chr5-159971902-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000679.4(ADRA1B):c.973C>A(p.Pro325Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000004 in 999,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

ADRA1B
NM_000679.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

Variant links:

Genes affected

ADRA1B (HGNC:278): (adrenoceptor alpha 1B) 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-1B-adrenergic receptor, which induces neoplastic transformation when transfected into NIH 3T3 fibroblasts and other cell lines. Thus, this normal cellular gene is identified as a protooncogene. This gene comprises 2 exons and a single large intron of at least 20 kb that interrupts the coding region. [provided by RefSeq, Jul 2008]

ADRA1B links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ADRA1B	NM_000679.4 link	c.973C>A	p.Pro325Thr	missense_variant	Exon 2 of 2	ENST00000306675.5	NP_000670.1	P35368
ADRA1B	XM_011534435.2 link	c.1081C>A	p.Pro361Thr	missense_variant	Exon 5 of 5		XP_011532737.1
ADRA1B	XM_047416776.1 link	c.1081C>A	p.Pro361Thr	missense_variant	Exon 6 of 6		XP_047272732.1
ADRA1B	XM_006714821.4 link	c.950-13769C>A		intron_variant	Intron 1 of 1		XP_006714884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRA1B	ENST00000306675.5 link	c.973C>A	p.Pro325Thr	missense_variant	Exon 2 of 2	1	NM_000679.4	ENSP00000306662.3		P35368

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000400

AC:

AN:

999550

Hom.:

Cov.:

AF XY:

0.00000207

AC XY:

AN XY:

483414

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000476

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.973C>A (p.P325T) alteration is located in exon 2 (coding exon 2) of the ADRA1B gene. This alteration results from a C to A substitution at nucleotide position 973, causing the proline (P) at amino acid position 325 to be replaced by a threonine (T). 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Benign

0.17

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.86

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.63

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.3

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.31

Sift

Benign

0.082

Sift4G

Benign

0.15

Polyphen

0.87

Vest4

0.53

MutPred

0.51

Loss of catalytic residue at P325 (P = 0.07);

MVP

0.83

MPC

1.2

ClinPred

0.99

GERP RS

1.5

Varity_R

0.56

gMVP

0.66

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over