rs61761869

chr14-94378529-G-Achr14-94378529-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000295.5(SERPINA1):c.1177C>T(p.Pro393Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P393T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:1
• Conservation: PhyloP100: 8.72

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94378528-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 14-94378529-G-A is Pathogenic according to our data. Variant chr14-94378529-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289135.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=9, Uncertain_significance=1}. Variant chr14-94378529-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.1177C>T	p.Pro393Ser	missense_variant	5/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1177C>T	p.Pro393Ser	missense_variant	5/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000290 AC: 73 AN: 251474 Hom.: 0 AF XY: 0.000353 AC XY: 48 AN XY: 135908

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000362 AC: 529 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.000385 AC XY: 280 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000433

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74428

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000563 Hom.: 1

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.00109

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:7 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 393 of the SERPINA1 protein (p.Pro393Ser). This variant is present in population databases (rs61761869, gnomAD 0.05%). This missense change has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 18024524, 27296815). ClinVar contains an entry for this variant (Variation ID: 289135). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508, 27296815). This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2784123, 10234508, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (81 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) with p.(Pro393Leu) having the highest allele count (14 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated reactive centre loop (RCL) within the Serpin domain (NCBI conserved domains; Pfam). (I) 0704 - Another missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. The p.(Pro393Leu) (alternatively known as P369L or MHeerlen) has previously been reported in at least 5 patients and has been suggested to result in extremely low AAT level and no liver disease (ClinVar; PMID: 26321041; 2784123; 27296815; 10234508). In addition, p.(Pro393His) has previously been reported in an adult female patient (compound heterozygote with the 'S' allele) suspected of having AATD however AAT serum level was normal (PMID: 31307431) and p.(Pro393Thr) was previously reported as pathogenic and as a variant of uncertain significance once each in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is also known as p.(Pro369Leu) in an alternative nomenclature or as the MWurzburg allele. It has previously been reported in at least 8 alpha-1-1-antitrypsin deficiency patients and is often referred to as a severe deficient allele (ClinVar; PMIDs: 27296815; 18024524; 18515255; 11474657; 19437508; 10878477). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro and in vivo functional studies have demonstrated that this variant results in intracellular transportation and secretion defects (PMID: 10234508; 22723858). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 13, 2017	The p.Pro393Ser variant in SERPINA1 (MWurzburg allele) has been reported in at l east 5 individuals with SERPINA1-related phenotypes, including alpha-1-antitryps in deficiency (AATD), asthma, elevated transaminases, and intrahepatic inclusion s (Poller 1999, Sexias 2001, Medicina 2009, Silva 2016, and Denden 2009). Three of these individuals were heterozygous, while 2 individuals with liver phenotype s were compound heterozygous. The variant segregated in at least 1 family member with low levels of alpha-1-antritrypsin and 2 members of 1 family with asthma ( Poller 1999, Denden 2009). In vitro and in vivo functional studies provide some evidence that the p.Pro393Ser variant may impact protein function; however, thes e types of assays may not accurately represent biological function (Poller 1999, Fra 2012). This variant has also been identified in 29/66728 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs61761869); however, this frequency is low enough to be consistent with a r ecessive carrier frequency. Furthermore, a different variant at the same positio n (p.Pro393Leu) has been classified as pathogenic by our laboratory, supporting that a change at this position may not be tolerated. In summary, although additi onal studies are required to fully establish its clinical significance, the p.Pr o393Ser variant is likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000295.4(SERPINA1):c.1177C>T(P393S) is a missense variant classified as a variant of uncertain significance in the context of alpha-1 antitrypsin deficiency. P393S has been observed in cases with relevant disease (PMID: 19437508, 18515255, 10878477, 10234508, 27296815, 21474916, 19654085). Functional assessments of this variant are available in the literature (PMID: 22723858, 10234508). P393S has been observed in population frequency databases (gnomAD: NFE 0.05%). In summary, there is insufficient evidence to classify NM_000295.4(SERPINA1):c.1177C>T(P393S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 17, 2018	The SERPINA1 c.1177C>T (p.Pro393Ser) variant, also referred to as Pi-M(Wurzburg), has been identified in a compound heterozygous state in three patients with alpha-1 antitrypsin deficiency (AATD) (Seixas et al. 2001; Medicina et al. 2009; Zorzetto et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.000513 in the European (non-Finnish) population of the Genome Aggregation Database. Poller et al. (1999) performed in vitro and in vivo functional studies and demonstrated that the p.Pro393Ser variant had defective intracellular transport and secretion into the bloodstream compared to the wild type AAT protein. The Pro393 residue is predicted to form part of a critical domain of the AAT protein. Based on the evidence, the p.Pro393Ser variant is classified as likely 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	Revvity Omics, Revvity	Feb 14, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SERPINA1: PM3:Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2023	Published functional studies demonstrate reduced alpha-1-antitrypsin secretion and a complete intracellular transport block (Fra et al., 2012; Poller et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as P369S or Mwurzburg allele using alternate nomenclature; This variant is associated with the following publications: (PMID: 31980526, 10234508, 27296815, 11474657, 31447099, 34426522, 22723858, 31661293, 21228398, 29882371) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2017	- -

SERPINA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2023

The SERPINA1 c.1177C>T variant is predicted to result in the amino acid substitution p.Pro393Ser. This variant has been reported to be pathogenic for autosomal recessive alpha1-antitrypsin deficiency (Giacopuzzi et al. 2018. PubMed ID: 29882371; Ortega et al. 2019. PubMed ID: 31661293). It is known as the M (Würzburg) allele in the literature. This variant is reported in 0.053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is reported as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D;D;D;D;D;D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;.;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D
Vest4		0.83
MVP		1.0
MPC		0.31
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.77

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: rs61761869; hg19: chr14-94844866;