rs1057519610

chr14-94379500-GGA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000295.5(SERPINA1):c.1027_1028del(p.Ser343ArgfsTer16) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic,other (no stars). Synonymous variant affecting the same amino acid position (i.e. S343S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SERPINA1 NM_000295.5 frameshift
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O:2
• Conservation: PhyloP100: 5.33

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 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-94379500-GGA-G is Pathogenic according to our data. Variant chr14-94379500-GGA-G is described in ClinVar as [Pathogenic, other]. Clinvar id is 17980.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-94379500-GGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.1027_1028del	p.Ser343ArgfsTer16	frameshift_variant	4/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1027_1028del	p.Ser343ArgfsTer16	frameshift_variant	4/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GeneReviews

May 01, 2014

- -

PI Q0(HONG KONG 1) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

PI NULL(HONG KONG 1) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519610; hg19: chr14-94845837;