rs28929472

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4

The NM_000295.5(SERPINA1):c.839A>T(p.Asp280Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic,other (★★). Synonymous variant affecting the same amino acid position (i.e. D280D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Pathogenic; other criteria provided, multiple submitters, no conflicts P:12O:5

Conservation

PhyloP100: 1.16

Publications

26 publications found

Variant links:

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

SERPINA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000295.5

PP5

Variant 14-94380949-T-A is Pathogenic according to our data. Variant chr14-94380949-T-A is described in ClinVar as Pathogenic|other. ClinVar VariationId is 17975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.25806603). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5 link	c.839A>T	p.Asp280Val	missense_variant	Exon 3 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9 link	c.839A>T	p.Asp280Val	missense_variant	Exon 3 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000473

AC:

119

AN:

251490

AF XY:

0.000478

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000545

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000370

AC:

541

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

257

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000626

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00321

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000337

AC:

375

AN:

1112010

Other (OTH)

AF:

0.000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000335

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41564

American (AMR)

AF:

0.000392

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68012

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000751

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000948

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:12Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Pathogenic:9

Mar 12, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PS3, PS4_M, PM3, PP3, PP5; Individual was compound heterozygous for SERPINA1 variants c.839A>T and c.1096G>A -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 280 of the SERPINA1 protein (p.Asp280Val). This variant is present in population databases (rs121912714, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-1 antitrypsin deficiency (AATD) (PMID: 2240842, 2787118, 2831367, 8364590, 15744045, 17906067, 26321041, 27296815). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp256Val, PI*Lowell allele, PI*Duarte allele, or PI*Null Cardiff allele. ClinVar contains an entry for this variant (Variation ID: 17975). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 2240842, 14767073, 15949707). For these reasons, this variant has been classified as Pathogenic. -

Mar 09, 2016

Counsyl

Significance:Likely 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. -

Aug 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SERPINA1 c.839A>T (p.Asp280Val) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SERPINA1 causing Alpha-1-Antitrypsin Deficiency (0.00047 vs 0.005), allowing no conclusion about variant significance. c.839A>T has been reported in the literature in multiple individuals affected with Alpha-1-Antitrypsin Deficiency (examples: Faber_1989, Holmes_1990,Grahm_2015, Silva_2016,Ortega_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant causes a protein folding defect (Jung_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14767073, 2240842, 2787118, 27296815, 31661293, 26321041). ClinVar contains an entry for this variant (Variation ID: 17975). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 07, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Aug 08, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2Other:1

Apr 30, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect due to impaired secretion of mutant protein (PMID: 15949707, 2240842); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14767073, 31661293, 2787118, 21474916, 8364590, 1504305, 25637381, 2606478, 2696185, 15744045, 2831367, 2240842, 17906067, 26321041, 29882371, 27296815, 26987331, 27264265, 31447099, 31980526, 34426522, 31589614, 34308104, 34828384, 15949707, 32191290) -

Jun 22, 2016

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SERPINA1 p.Asp280Val variant, often referred to as the Plowell protein variant, was identified in 12 of 248 proband chromosomes (2 homozygotes, frequency: 0.048) from individuals or families with alpha1-antitrypsin deficiency (AATD) and was not identified in 1500 control chromosomes from individuals with normal AAT serum levels (Graham_2015_PMID:26321041; Corda_2011_PMID:21474916; Bornhorst_2007_PMID:17906067). The variant was also identified in dbSNP (ID: rs121912714), LOVD 3.0 and in ClinVar (classified as pathogenic by Trillium Health Partners Credit Valley Hospital, likely pathogenic by Counsyl and CSER_CC_NCGL, University of Washington Medical Center, and 'other' by EGL Genetic Diagnostics). The variant was not identified in Cosmic. The variant was identified in control databases in 129 of 282876 chromosomes at a frequency of 0.000456 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 35 of 10370 chromosomes (freq: 0.003375), Latino in 20 of 35438 chromosomes (freq: 0.000564), Other in 4 of 7226 chromosomes (freq: 0.000554), European (non-Finnish) in 68 of 129190 chromosomes (freq: 0.000526) and South Asian in 2 of 30616 chromosomes (freq: 0.000065); it was not observed in the African, East Asian and European (Finnish) populations. Functional studies of the D280V variant have suggested increased intracellular protein degradation and have demonstrated delayed secretion of the AAT protein, with only the secreted form producing a stable SDS-complex with elastase while the intracellular form demonstrated reduced ability to form a stable complex. However little differences in stability to urea denaturation were observed compared to the wildtype (Ray_2006_PMID: 15949707; Holmes_1990_PMID:2240842). Another functional study found that the D280V variant caused delayed protein folding, however the stability and inhibitory activity of the protein was similar to wildtype once protein folding did occur (Jung_2004_PMID: 14767073). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp280 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

SERPINA1-related disorder

Pathogenic:1

Feb 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SERPINA1 c.839A>T variant is predicted to result in the amino acid substitution p.Asp280Val. This variant has been reported to be causative for autosomal recessive alpha-1-antitrypsin deficiency (Silva et al 2016. PubMed ID: 27296815, reported as p.Asp256Val; Graham et al 2015. PubMed ID: 26321041). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

PI Q0(CARDIFF)

Other:1

Jul 15, 2016

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PI P(DUARTE)

Other:1

Jul 15, 2016

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PI NULL(CARDIFF)

Other:1

Jul 15, 2016

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PI P(LOWELL)

Other:1

Jul 15, 2016

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

D;D;D;D;D;D;D;D;D;.

Eigen

Benign

0.12

Eigen_PC

Benign

-0.061

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.92

.;.;.;D;.;.;.;.;.;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.26

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;M;M;M;M

PhyloP100

1.2

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-7.2

D;D;D;D;D;.;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;D;D;D;D;.;D;D;D;D

Sift4G

Uncertain

0.049

D;D;D;D;D;.;D;D;D;T

Polyphen

0.98

D;D;D;D;D;D;D;D;D;P

Vest4

0.79

MVP

0.94

MPC

0.34

ClinPred

0.22

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.71

gMVP

0.64

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over