rs28929472
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000295.5(SERPINA1):c.839A>T(p.Asp280Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,other (★★). Synonymous variant affecting the same amino acid position (i.e. D280D) has been classified as Benign.
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00037 ( 1 hom. )
Consequence
SERPINA1
NM_000295.5 missense
NM_000295.5 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 1.16
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-94380949-T-A is Pathogenic according to our data. Variant chr14-94380949-T-A is described in ClinVar as [Likely_pathogenic, other]. Clinvar id is 17975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94380949-T-A is described in Lovd as [Likely_benign]. Variant chr14-94380949-T-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.25806603). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SERPINA1 | NM_000295.5 | c.839A>T | p.Asp280Val | missense_variant | 3/5 | ENST00000393087.9 | NP_000286.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SERPINA1 | ENST00000393087.9 | c.839A>T | p.Asp280Val | missense_variant | 3/5 | 1 | NM_000295.5 | ENSP00000376802.4 |
Frequencies
GnomAD3 genomes 0.000335 AC: 51AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000473 AC: 119AN: 251490Hom.: 0 AF XY: 0.000478 AC XY: 65AN XY: 135918
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GnomAD4 exome AF: 0.000370 AC: 541AN: 1461892Hom.: 1 Cov.: 31 AF XY: 0.000353 AC XY: 257AN XY: 727248
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GnomAD4 genome 0.000335 AC: 51AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74448
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ClinVar
Significance: Pathogenic/Likely pathogenic; other
Submissions summary: Pathogenic:12Other:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alpha-1-antitrypsin deficiency Pathogenic:9
| Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 09, 2016 | - - |
| Pathogenic, no assertion criteria provided | curation | Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital | Dec 08, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 07, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Mar 12, 2024 | ACMG Criteria: PS3, PS4_M, PM3, PP3, PP5; Individual was compound heterozygous for SERPINA1 variants c.839A>T and c.1096G>A - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Aug 08, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 280 of the SERPINA1 protein (p.Asp280Val). This variant is present in population databases (rs121912714, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-1 antitrypsin deficiency (AATD) (PMID: 2240842, 2787118, 2831367, 8364590, 15744045, 17906067, 26321041, 27296815). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp256Val, PI*Lowell allele, PI*Duarte allele, or PI*Null Cardiff allele. ClinVar contains an entry for this variant (Variation ID: 17975). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 2240842, 14767073, 15949707). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 01, 2024 | Variant summary: SERPINA1 c.839A>T (p.Asp280Val) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SERPINA1 causing Alpha-1-Antitrypsin Deficiency (0.00047 vs 0.005), allowing no conclusion about variant significance. c.839A>T has been reported in the literature in multiple individuals affected with Alpha-1-Antitrypsin Deficiency (examples: Faber_1989, Holmes_1990,Grahm_2015, Silva_2016,Ortega_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant causes a protein folding defect (Jung_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14767073, 2240842, 2787118, 27296815, 31661293, 26321041). ClinVar contains an entry for this variant (Variation ID: 17975). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2023 | Published functional studies demonstrate a damaging effect due to impaired secretion of mutant protein (PMID: 15949707, 2240842); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14767073, 31661293, 2787118, 21474916, 8364590, 1504305, 25637381, 2606478, 2696185, 15744045, 2831367, 2240842, 17906067, 26321041, 29882371, 27296815, 26987331, 27264265, 31447099, 31980526, 34426522, 31589614, 34308104, 34828384, 15949707, 27535533) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The SERPINA1 p.Asp280Val variant, often referred to as the Plowell protein variant, was identified in 12 of 248 proband chromosomes (2 homozygotes, frequency: 0.048) from individuals or families with alpha1-antitrypsin deficiency (AATD) and was not identified in 1500 control chromosomes from individuals with normal AAT serum levels (Graham_2015_PMID:26321041; Corda_2011_PMID:21474916; Bornhorst_2007_PMID:17906067). The variant was also identified in dbSNP (ID: rs121912714), LOVD 3.0 and in ClinVar (classified as pathogenic by Trillium Health Partners Credit Valley Hospital, likely pathogenic by Counsyl and CSER_CC_NCGL, University of Washington Medical Center, and 'other' by EGL Genetic Diagnostics). The variant was not identified in Cosmic. The variant was identified in control databases in 129 of 282876 chromosomes at a frequency of 0.000456 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 35 of 10370 chromosomes (freq: 0.003375), Latino in 20 of 35438 chromosomes (freq: 0.000564), Other in 4 of 7226 chromosomes (freq: 0.000554), European (non-Finnish) in 68 of 129190 chromosomes (freq: 0.000526) and South Asian in 2 of 30616 chromosomes (freq: 0.000065); it was not observed in the African, East Asian and European (Finnish) populations. Functional studies of the D280V variant have suggested increased intracellular protein degradation and have demonstrated delayed secretion of the AAT protein, with only the secreted form producing a stable SDS-complex with elastase while the intracellular form demonstrated reduced ability to form a stable complex. However little differences in stability to urea denaturation were observed compared to the wildtype (Ray_2006_PMID: 15949707; Holmes_1990_PMID:2240842). Another functional study found that the D280V variant caused delayed protein folding, however the stability and inhibitory activity of the protein was similar to wildtype once protein folding did occur (Jung_2004_PMID: 14767073). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp280 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. - |
| other, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 22, 2016 | - Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). |
SERPINA1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 20, 2024 | The SERPINA1 c.839A>T variant is predicted to result in the amino acid substitution p.Asp280Val. This variant has been reported to be causative for autosomal recessive alpha-1-antitrypsin deficiency (Silva et al 2016. PubMed ID: 27296815, reported as p.Asp256Val; Graham et al 2015. PubMed ID: 26321041). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. - |
PI Q0(CARDIFF) Other:1
| other, no assertion criteria provided | literature only | OMIM | Jul 15, 2016 | - - |
PI P(DUARTE) Other:1
| other, no assertion criteria provided | literature only | OMIM | Jul 15, 2016 | - - |
PI NULL(CARDIFF) Other:1
| other, no assertion criteria provided | literature only | OMIM | Jul 15, 2016 | - - |
PI P(LOWELL) Other:1
| other, no assertion criteria provided | literature only | OMIM | Jul 15, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D;D;D;D;D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
.;.;.;D;.;.;.;.;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M;M;M
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D;T
Polyphen
D;D;D;D;D;D;D;D;D;P
Vest4
MVP
MPC
0.34
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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