chr14-94378547-C-CG
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000393087.9(SERPINA1):βc.1158_1159insCβ(p.Glu387ArgfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P386P) has been classified as Likely benign.
Frequency
Genomes: π 0.000040 ( 0 hom., cov: 33)
Exomes π: 0.000016 ( 0 hom. )
Consequence
SERPINA1
ENST00000393087.9 frameshift
ENST00000393087.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.35
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 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-94378547-C-CG is Pathogenic according to our data. Variant chr14-94378547-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SERPINA1 | NM_000295.5 | c.1158_1159insC | p.Glu387ArgfsTer14 | frameshift_variant | 5/5 | ENST00000393087.9 | NP_000286.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SERPINA1 | ENST00000393087.9 | c.1158_1159insC | p.Glu387ArgfsTer14 | frameshift_variant | 5/5 | 1 | NM_000295.5 | ENSP00000376802 | P1 |
Frequencies
GnomAD3 genomes 0.0000395 AC: 6AN: 151844Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251306Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135826
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461796Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727206
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GnomAD4 genome 0.0000395 AC: 6AN: 151844Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3AN XY: 74162
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alpha-1-antitrypsin deficiency Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 11, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects SERPINA1 function (PMID: 9070606). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 188845). This premature translational stop signal has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 7977369, 9070606, 11334395, 22016686). This variant is present in population databases (rs764325655, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Glu387Argfs*14) in the SERPINA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the SERPINA1 protein. - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 21, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 28, 2023 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at