14-94378575-TA-TAA

Position:

• chr14-94378575-TA-TAA

Variant summary

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

The ENST00000393087.9(SERPINA1):​c.1130_1131insT​(p.Leu377PhefsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SERPINA1 ENST00000393087.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.870

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 14-94378575-T-TA is Pathogenic according to our data. Variant chr14-94378575-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 552891.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.1130_1131insT	p.Leu377PhefsTer24	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.1130_1131insT	p.Leu377PhefsTer24	frameshift_variant	5/5	1	NM_000295.5	ENSP00000376802	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251418 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: 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	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the SERPINA1 protein. Other variant(s) that disrupt this region (p.Glu387Argfs*14) have been determined to be pathogenic (PMID: 9070606, 11334395, 22016686). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been reported to affect SERPINA1 protein function (PMID: 2539391). This variant has been observed in individual(s) with alpha-1-antitrypsin deficiency (PMID: 2539391, 21457231). It has also been observed to segregate with disease in related individuals. This variant is also known as Null Mattawa, L353fsX376, c.1126->T and Q0nancy in the literature. ClinVar contains an entry for this variant (Variation ID: 552891). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the SERPINA1 gene (p.Leu377Phefs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acids of the SERPINA1 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Child Health and Human Development Program, Research Institute of the McGill University Health Center	-	The homozygous duplication of a single nucleotide [c.1130dup (p.Leu377fs)] in SERPINA1 was identified in a 65 year old female of Latin American origin being treated for emphysema. Her AAT level was 0.10 g/L. The AAT reference range at our institution is 0.99-2.59 g/L. -

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: rs763023697; hg19: chr14-94844912;