rs121912714
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 Likely benign.
Frequency
Consequence
NM_000295.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINA1 | NM_000295.5 | c.839A>T | p.Asp280Val | missense_variant | 3/5 | ENST00000393087.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINA1 | ENST00000393087.9 | c.839A>T | p.Asp280Val | missense_variant | 3/5 | 1 | NM_000295.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000335 AC: 51AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000473 AC: 119AN: 251490Hom.: 0 AF XY: 0.000478 AC XY: 65AN XY: 135918
GnomAD4 exome AF: 0.000370 AC: 541AN: 1461892Hom.: 1 Cov.: 31 AF XY: 0.000353 AC XY: 257AN XY: 727248
GnomAD4 genome ? AF: 0.000335 AC: 51AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74448
ClinVar
Submissions by phenotype
Alpha-1-antitrypsin deficiency Pathogenic:8
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 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 09, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 07, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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, no assertion criteria provided | curation | Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital | Dec 08, 2014 | - - |
Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Aug 08, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
not provided Pathogenic:2Other:1
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). |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2021 | Published functional studies demonstrate a damaging effect due to impaired secretion of mutant protein (Holmes et al., 1990; Ray et al., 2005); This variant is associated with the following publications: (PMID: 27535533, 31589614, 31980526, 31447099, 27264265, 26987331, 27296815, 29882371, 2787118, 2240842, 26321041, 17906067, 2831367, 15744045, 2696185, 2606478, 25637381, 1504305, 8364590, 15949707, 21474916, 14767073) - |
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. - |
SERPINA1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at