rs775982338

Variant names:

• chr14-94383008-GAGA-G
• rs775982338
• NM_000295.5:c.227_229delTCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_000295.5(SERPINA1):​c.227_229delTCT​(p.Phe76del) variant causes a disruptive 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 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 8.82
• Publications: 16 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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000295.5
• PM4: Nonframeshift variant in NON repetitive region in NM_000295.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 14-94383008-GAGA-G is Pathogenic according to our data. Variant chr14-94383008-GAGA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 315028.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.227_229delTCT	p.Phe76del	disruptive_inframe_deletion	Exon 2 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.227_229delTCT	p.Phe76del	disruptive_inframe_deletion	Exon 2 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.227_229delTCT	p.Phe76del	disruptive_inframe_deletion	Exon 4 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.227_229delTCT	p.Phe76del	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.227_229delTCT	p.Phe76del	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.227_229delTCT	p.Phe76del	disruptive_inframe_deletion	Exon 4 of 7	ENSP00000376803.4

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

GnomAD2 exomes AF: 0.000144 AC: 36 AN: 250678 AF XY: 0.000118

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.000313 AC: 14 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.000632 AC: 25 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5754

European-Non Finnish (NFE) AF: 0.000186 AC: 206 AN: 1108838

Other (OTH) AF: 0.000249 AC: 15 AN: 60222

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

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68042

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

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:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 08, 2014

Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

amino acid deletion

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of variants on gene product 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.

Nov 20, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Feb 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 08, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 28, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid(s) in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Also known as p.Phe52del or the PI*Mmalton allele; This variant is associated with the following publications: (PMID: 3491442, 34426522, 31589614, 37685316, 38814878, 37277845, 38791420, 24183282, 29882371, 34308104, 27882547, 19747908, 26321041, 2786335, 33597804, 32076552, 35263815, 39286412, 34638908, DeCurtis2024[CaseReport], 36797151, 6600898, 24969923, 33331634, 2788166, 36630963, 38637533, 27296815, 15744045, 22291048, 24713750)

SERPINA1-related disorder Pathogenic:1

Jul 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 15, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=52/48	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs775982338; hg19: chr14-94849345;