rs775982338

chr14-94383008-GAGA-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_000295.5(SERPINA1):c.227_229del(p.Phe76del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,610,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 8.82

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000295.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000295.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 14-94383008-GAGA-G is Pathogenic according to our data. Variant chr14-94383008-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 315028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94383008-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.227_229del	p.Phe76del	inframe_deletion	2/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.227_229del	p.Phe76del	inframe_deletion	2/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 250678 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135472

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000182 AC: 265 AN: 1458068 Hom.: 0 AF XY: 0.000168 AC XY: 122 AN XY: 724486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000632

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152376 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74508

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000249

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	amino acid deletion -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SERPINA1 c.227_229delTCT (p.Phe76del) variant is an inframe deletion variant which is often described in the literature as p.Phe51del, p.Phe52del, PI*MMalton, or MMalton. The p.Phe76del variant has been reported in at least seven studies in 16 patients with reduced serum alpha-1 antitrypsin (AAT) concentrations and other phenotypic features consistent with alpha-1 antitrypsin deficiency, including in one in a homozygous state and in 15 in a compound heterozygous state (Sproule et al. 1983; Allen et al 1986; Curiek et al. 1989; Frazier et al. 1989; Lara et al. 2013; Suh-Lailam et al. 2014; Beletic et al 2014). The p.Phe76del variant has also been found in a heterozygous state in at least three individuals with reduced alpha-1 antitrypsin concentrations and normal pulmonary function. The variant was absent from 311 controls and is reported at a frequency of 0.00069 in the East Asian population of the Exome Aggregation Consortium. Curiel et al. (1989) demonstrated abnormal intracellular accumulation of newly synthesized AAT protein in an individual homozygous for the p.Phe76del variant, with inflammation, mild fibrosis, and intrahepatocyte AAT protein accumulation revealed on liver biopsy. Furthermore, functional analysis by retroviral gene transfer of AAT cDNA with the variant into murine cells demonstrated that abnormal intracellular accumulation of AAT protein occurred (Curiel et al 1989). Based on the collective evidence, the p.Phe76del variant is classified as pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 20, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This variant, c.227_229del, results in the deletion of 1 amino acid(s) of the SERPINA1 protein (p.Phe76del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775982338, gnomAD 0.04%). This variant has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 2788166, 3491442, 6600898, 15744045, 22291048, 24183282, 27296815, 27882547). It has also been observed to segregate with disease in related individuals. This variant is also known as PI*Mmalton or Phe52del. ClinVar contains an entry for this variant (Variation ID: 315028). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SERPINA1 function (PMID: 2788166). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

SERPINA1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2023

The SERPINA1 c.227_229delTCT variant is predicted to result in an in-frame deletion (p.Phe76del). This variant, also described as p.Phe52del and the PI*Mmalton allele, has been reported in the homozygous and compound heterozygous states to be pathogenic for alpha-1-antitrypsin deficiency (Curiel et al. 1989. PubMed ID: 2788166; Fraizer et al. 1989. PubMed ID: 2786335; Rodriguez-Frias et al. 2012. PubMed ID: 22291048; Silva et al. 2016. PubMed ID: 27296815). This variant produces a poorly folded protein and is associated with an increased risk of pulmonary emphysema and liver disease (Curiel et al. 1989. PubMed ID: 2788166; Giacopuzzi et al. 2018. PubMed ID: 29882371; Silva et al. 2016. PubMed ID: 27296815). The mode of inheritance of SERPINA1-related disease is complicated by co-dominance. The PI*Mmalton allele has been detected in the heterozygous state in healthy individuals of advanced age; however, heterozygotes are at an increased risk of respiratory complications, which is elevated by cigarette smoke exposure (Aiello et al. 2020. PubMedID 32076552). A homozygous individual was reported with liver fibrosis and cirhosis, and compound heterozygosity with the Z allele was associated with chronic pulmonary obstructive disease (Joly et al. 2015. PubMed ID: 26446624). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

PI M(MALTON) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 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: rs775982338; hg19: chr14-94849345;