chr8-26864566-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000680.4(ADRA1A):c.404C>T(p.Pro135Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
ADRA1A
NM_000680.4 missense
NM_000680.4 missense
Scores
9
7
2
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.864
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADRA1A | NM_000680.4 | c.404C>T | p.Pro135Leu | missense_variant | 2/3 | ENST00000380573.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADRA1A | ENST00000380573.4 | c.404C>T | p.Pro135Leu | missense_variant | 2/3 | 2 | NM_000680.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251262Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135792
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GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727208
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 24, 2023 | The c.404C>T (p.P135L) alteration is located in exon 1 (coding exon 1) of the ADRA1A gene. This alteration results from a C to T substitution at nucleotide position 404, causing the proline (P) at amino acid position 135 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;L;L;L;L
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;D;D;D;.
Vest4
MutPred
Loss of glycosylation at T136 (P = 0.1079);Loss of glycosylation at T136 (P = 0.1079);Loss of glycosylation at T136 (P = 0.1079);Loss of glycosylation at T136 (P = 0.1079);Loss of glycosylation at T136 (P = 0.1079);Loss of glycosylation at T136 (P = 0.1079);Loss of glycosylation at T136 (P = 0.1079);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at