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rs28929474

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000295.5(SERPINA1):c.1096G>C(p.Glu366Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,882 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 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: 0.0000048 ( 0 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

3
11
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.27
Variant links:
Genes affected
SERPINA1 (HGNC:8941): (serpin family A member 1) The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_000295.5
PM2
Very rare variant in population databases, with high coverage;
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
SERPINA1NM_000295.5 linkuse as main transcriptc.1096G>C p.Glu366Gln missense_variant 5/5 ENST00000393087.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SERPINA1ENST00000393087.9 linkuse as main transcriptc.1096G>C p.Glu366Gln missense_variant 5/51 NM_000295.5 P1P01009-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251360
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461882
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

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 submitterclinical testingInvitaeSep 09, 2023This 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. 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. ClinVar contains an entry for this variant (Variation ID: 1492979). This variant has not been reported in the literature in individuals affected with SERPINA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Uncertain
0.029
T
BayesDel_noAF
Uncertain
0.070
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;D;D;D;D;D;D;D;D
Eigen
Uncertain
0.32
Eigen_PC
Benign
0.058
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Benign
0.055
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
3.8
H;H;H;H;H;H;H;H;H
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-2.6
D;D;D;D;D;.;D;D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0020
D;D;D;D;D;.;D;D;D
Sift4G
Uncertain
0.0050
D;D;D;D;D;.;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D;D;D
Vest4
0.65
MutPred
0.84
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
0.99
MPC
0.31
ClinPred
0.88
D
GERP RS
3.0
Varity_R
0.78
gMVP
0.72

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28929474; hg19: chr14-94844947; API