rs864622043

chr14-94378590-AGCAGCTTC-ATGTTTTT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000295.5(SERPINA1):c.1108_1115delinsAAAAACA(p.Glu370LysfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINA1 NM_000295.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.27

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]

ACMG classification

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 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-94378591-GCAGCTTC-TGTTTTT is Pathogenic according to our data. Variant chr14-94378591-GCAGCTTC-TGTTTTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.1108_1115delinsAAAAACA	p.Glu370LysfsTer8	frameshift_variant	5/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1108_1115delinsAAAAACA	p.Glu370LysfsTer8	frameshift_variant	5/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	This sequence change creates a premature translational stop signal (p.Glu370Lysfs*8) in the SERPINA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the SERPINA1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SERPINA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 219353). This variant disrupts a region of the SERPINA1 protein in which other variant(s) (p.Glu387Argfs*14) have been determined to be pathogenic (PMID: 9070606, 11334395, 22016686; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Child Health and Human Development Program, Research Institute of the McGill University Health Center	-	The deletion/insertion [c.1108_1115delinsAAAAACA (p.Glu370Lysfs*31)] in SERPINA1 was identified in a 35 year old male with history of smoking and being treated for bullous emphysema with intravenous AAT replacement therapy. His AAT levels were 0.80 g/L, 0.82 g/L and 0.60 g/L. The AAT reference range at our institution is 0.99-2.59 g/L. AAT level was consistent with one functioning allele, which matches the heterozygous [c.1108_1115delinsAAAAACA (p.Glu370Lysfs*31)] detected by sequencing. -
Pathogenic, criteria provided, single submitter	clinical testing	HerediLab, Inc.	Nov 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864622043; hg19: chr14-94844928;