rs864622043

Variant names:

• chr14-94378591-GCAGCTTC-TGTTTTT
• rs864622043
• NM_000295.5:c.1108_1115delGAAGCTGCinsAAAAACA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000295.5(SERPINA1):​c.1108_1115delGAAGCTGCinsAAAAACA​(p.Glu370LysfsTer8) variant causes a frameshift, missense 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, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.27
• Publications: 1 publications found

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]

SERPINA1 Gene-Disease associations (from GenCC):

• alpha 1-antitrypsin deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 14 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 219353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.1108_1115delGAAGCTGCinsAAAAACA	p.Glu370LysfsTer8	frameshift missense	Exon 5 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.1108_1115delGAAGCTGCinsAAAAACA	p.Glu370LysfsTer8	frameshift missense	Exon 5 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.1108_1115delGAAGCTGCinsAAAAACA	p.Glu370LysfsTer8	frameshift missense	Exon 7 of 7	NP_001002236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.1108_1115delGAAGCTGCinsAAAAACA	p.Glu370LysfsTer8	frameshift missense	Exon 5 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.1108_1115delGAAGCTGCinsAAAAACA	p.Glu370LysfsTer8	frameshift missense	Exon 5 of 5	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.1108_1115delGAAGCTGCinsAAAAACA	p.Glu370LysfsTer8	frameshift missense	Exon 7 of 7	ENSP00000376803.4

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

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Alpha-1-antitrypsin deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

Splicing

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

Other links and lift over

dbSNP: rs864622043; hg19: chr14-94844928;