rs28929474
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate
The NM_000295(SERPINA1):c.1096G>C(p.Glu366Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E366K) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
SERPINA1
NM_000295 missense
NM_000295 missense
Scores
3
11
4
Clinical Significance
Conservation
PhyloP100: 5.27
Links
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000295
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr14-94378610-C-T is described in ClinVar as [Pathogenic, risk_factor]. Clinvar id is 17967. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
?
Variant 14:94378610-C>G is Pathogenic according to our data. Variant chr14-94378610-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1492979. Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINA1 | NM_000295.5 | c.1096G>C | p.Glu366Gln | missense_variant | 5/5 | ENST00000393087.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINA1 | ENST00000393087.9 | c.1096G>C | p.Glu366Gln | missense_variant | 5/5 | 1 | NM_000295.5 | P1 |
Frequencies
GnomAD3 genomesCov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251360Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135856
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461882Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727244
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Alpha-1-antitrypsin deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 366 of the SERPINA1 protein (p.Glu366Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SERPINA1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SERPINA1 protein function. This variant disrupts the p.Glu366 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 3500183, 9569237, 19083091). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D;D;D;D;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;H;H;H;H
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;.;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;.;D;D;D
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D
Polyphen
D;D;D;D;D;D;D;D;D
Vest4
MutPred
Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);Gain of catalytic residue at D365 (P = 0.0327);
MVP
MPC
0.31
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out SpliceAI and Pangolin per-transcript scores at