rs863225263
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000295.5(SERPINA1):βc.227_229delβ(p.Phe76del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,610,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.00018 ( 0 hom., cov: 33)
Exomes π: 0.00018 ( 0 hom. )
Consequence
SERPINA1
NM_000295.5 inframe_deletion
NM_000295.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.82
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 13 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000295.5
PM2
?
Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_000295.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
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Variant 14-94383008-GAGA-G is Pathogenic according to our data. Variant chr14-94383008-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 315028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94383008-GAGA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINA1 | NM_000295.5 | c.227_229del | p.Phe76del | inframe_deletion | 2/5 | ENST00000393087.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINA1 | ENST00000393087.9 | c.227_229del | p.Phe76del | inframe_deletion | 2/5 | 1 | NM_000295.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152258Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000144 AC: 36AN: 250678Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135472
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GnomAD4 exome AF: 0.000182 AC: 265AN: 1458068Hom.: 0 AF XY: 0.000168 AC XY: 122AN XY: 724486
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GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152376Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74508
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alpha-1-antitrypsin deficiency Pathogenic:5Other:1
Pathogenic, no assertion criteria provided | curation | Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital | Dec 08, 2014 | amino acid deletion - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The SERPINA1 c.227_229delTCT (p.Phe76del) variant is an inframe deletion variant which is often described in the literature as p.Phe51del, p.Phe52del, PI*MMalton, or MMalton. The p.Phe76del variant has been reported in at least seven studies in 16 patients with reduced serum alpha-1 antitrypsin (AAT) concentrations and other phenotypic features consistent with alpha-1 antitrypsin deficiency, including in one in a homozygous state and in 15 in a compound heterozygous state (Sproule et al. 1983; Allen et al 1986; Curiek et al. 1989; Frazier et al. 1989; Lara et al. 2013; Suh-Lailam et al. 2014; Beletic et al 2014). The p.Phe76del variant has also been found in a heterozygous state in at least three individuals with reduced alpha-1 antitrypsin concentrations and normal pulmonary function. The variant was absent from 311 controls and is reported at a frequency of 0.00069 in the East Asian population of the Exome Aggregation Consortium. Curiel et al. (1989) demonstrated abnormal intracellular accumulation of newly synthesized AAT protein in an individual homozygous for the p.Phe76del variant, with inflammation, mild fibrosis, and intrahepatocyte AAT protein accumulation revealed on liver biopsy. Furthermore, functional analysis by retroviral gene transfer of AAT cDNA with the variant into murine cells demonstrated that abnormal intracellular accumulation of AAT protein occurred (Curiel et al 1989). Based on the collective evidence, the p.Phe76del variant is classified as pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This variant, c.227_229del, results in the deletion of 1 amino acid(s) of the SERPINA1 protein (p.Phe76del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775982338, gnomAD 0.04%). This variant has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 2788166, 3491442, 6600898, 15744045, 22291048, 24183282, 27296815, 27882547). It has also been observed to segregate with disease in related individuals. This variant is also known as PI*Mmalton or Phe52del. ClinVar contains an entry for this variant (Variation ID: 315028). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SERPINA1 function (PMID: 2788166). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 20, 2015 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 08, 2017 | - - |
SERPINA1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 22, 2023 | The SERPINA1 c.227_229delTCT variant is predicted to result in an in-frame deletion (p.Phe76del). This variant, also described as p.Phe52del and the PI*Mmalton allele, has been reported in the homozygous and compound heterozygous states to be pathogenic for alpha-1-antitrypsin deficiency (Curiel et al. 1989. PubMed ID: 2788166; Fraizer et al. 1989. PubMed ID: 2786335; Rodriguez-Frias et al. 2012. PubMed ID: 22291048; Silva et al. 2016. PubMed ID: 27296815). This variant produces a poorly folded protein and is associated with an increased risk of pulmonary emphysema and liver disease (Curiel et al. 1989. PubMed ID: 2788166; Giacopuzzi et al. 2018. PubMed ID: 29882371; Silva et al. 2016. PubMed ID: 27296815). The mode of inheritance of SERPINA1-related disease is complicated by co-dominance. The PI*Mmalton allele has been detected in the heterozygous state in healthy individuals of advanced age; however, heterozygotes are at an increased risk of respiratory complications, which is elevated by cigarette smoke exposure (Aiello et al. 2020. PubMedID 32076552). A homozygous individual was reported with liver fibrosis and cirhosis, and compound heterozygosity with the Z allele was associated with chronic pulmonary obstructive disease (Joly et al. 2015. PubMed ID: 26446624). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. - |
PI M(MALTON) Other:1
other, no assertion criteria provided | literature only | OMIM | Jul 15, 2016 | - - |
Computational scores
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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