dbSNP rs17580: SERPINA1:p.Glu288Val (chr14-94380925-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received 1 ACMG points: 9P and 8B. BA1PS3PP3PP5_Strong

The NM_000295.5(SERPINA1):c.863A>T (p.Glu288Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0364 (AC=58,691) in the gnomAD database across 1,614,182 control chromosomes, including 1,342 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0521. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000389650: Curiel et al. (1989) demonstrated that the p.Glu288Val variant results in intracellular degradation of AAT protein prior to secretion." and additional evidence is available in ClinVar. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.029 ( 106 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1236 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Pathogenic/Pathogenic, low penetrance; other criteria provided, multiple submitters, no conflicts P:30U:1O:7

Conservation

PhyloP100: 6.46

Publications

172 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia
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

new If you want to explore the variant's impact on the transcript NM_000295.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PS3

Well-established functional study supports damaging effect (PS3); SCV000389650: Curiel et al. (1989) demonstrated that the p.Glu288Val variant results in intracellular degradation of AAT protein prior to secretion.; SCV000538062: The S allele has been shown to cause reduced cellular secretion of alpha 1AT because the newly synthesized S-type alpha 1AT protein is degraded intracellularly prior to secretion (Curiel et al., 1989).; SCV000630393: Experimental studies have shown that this variant results in reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro (PMID: 2567291), and causes lower expression as well as secretion in blood (PMID: 2567291, 22426792).; SCV002556452: "Well-established functional studies show a deleterious effect of this variant" (PMID:2567291); SCV002768380: The S allele has previously been shown to result in intracellular protein degradation (PMID: 15978931). (SP); SCV003844608: Experimental studies have shown this variant to result in reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro, which causes lower expression as well as secretion in blood (Curiel_1999).; SCV004812555: In silico modelling and in vitro assays using human blood monocytes and mouse fibroblasts showed that the mutant protein is more susceptible to intracellular polymerisation and degradation leading to reduced secretion when compared to the wildtype protein; PMID:3257660; SCV000568767: Results in reduced cellular secretion of alpha-1 antitrypsin as the S-type alpha-1 antitrypsin protein is degraded intracellularly prior to secretion (Curiel et al., 1989; Ferrarotti et al., 2012); SCV001552729: Functional studies of the variant have shown to cause reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro and to cause lower expression as well as secretion of alpha-1 antitrypsin in blood samples (Curiel_1989_PMID: 2567291; Ferraroti_2012_PMID:22426792).; SCV002688491: "In vitro studies demonstrate that this mutant allele results in reduced AAT levels due to intracellular degradation and decreased secretion of the protein (Curiel, 1989)."

PP3

Splicing predictors (SpliceAI/dbscSNV) support splicing impact — supporting computational evidence (PP3); Splicing verdict: pathogenic (Supporting).; Germline computational verdict: pathogenic (Supporting).

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.0521 — exceeds 5%% threshold (BA1 applied)

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA1	NM_000295.5	MANE Select	c.863A>T	p.Glu288Val	missense	Exon 3 of 5	NP_000286.3
SERPINA1	NM_001002235.3		c.863A>T	p.Glu288Val	missense	Exon 3 of 5	NP_001002235.1	E9KL23
SERPINA1	NM_001002236.3		c.863A>T	p.Glu288Val	missense	Exon 5 of 7	NP_001002236.1	E9KL23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.863A>T	p.Glu288Val	missense	Exon 3 of 5	ENSP00000376802.4	P01009-1
SERPINA1	ENST00000355814.8	TSL:1	c.863A>T	p.Glu288Val	missense	Exon 3 of 5	ENSP00000348068.4	P01009-1
SERPINA1	ENST00000393088.8	TSL:1	c.863A>T	p.Glu288Val	missense	Exon 5 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4376

AN:

152202

Hom.:

106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00880

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0553

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0468

GnomAD2 exomes

AF:

0.0233

AC:

5859

AN:

251480

AF XY:

0.0233

show subpopulations

Gnomad AFR exome

AF:

0.00794

Gnomad AMR exome

AF:

0.0301

Gnomad ASJ exome

AF:

0.0137

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00845

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0342

GnomAD4 exome

AF:

0.0372

AC:

54315

AN:

1461862

Hom.:

1236

Cov.:

AF XY:

0.0360

AC XY:

26152

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00642

AC:

215

AN:

33480

American (AMR)

AF:

0.0323

AC:

1443

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0140

AC:

366

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00841

AC:

449

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0448

AC:

49871

AN:

1111986

Other (OTH)

AF:

0.0324

AC:

1956

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

3000

5999

8999

11998

14998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1896

3792

5688

7584

9480

<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:

0.0287

AC:

4376

AN:

152320

Hom.:

106

Cov.:

AF XY:

0.0275

AC XY:

2046

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00878

AC:

365

AN:

41590

American (AMR)

AF:

0.0552

AC:

844

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00828

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0416

AC:

2830

AN:

68008

Other (OTH)

AF:

0.0464

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

221

441

662

882

1103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0340

Hom.:

Bravo

AF:

0.0325

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0351

EpiControl

AF:

0.0392

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0000160

AC:

AN:

122720

Turkish Variome

AF:

0.00343

AC:

AN:

6714

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0705

AC:

165

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Pathogenic, low penetrance; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha-1-antitrypsin deficiency (21)

not provided (9)

Autosomal recessive SERPINA1-related disorders (1)

Chronic obstructive pulmonary disease;C0221757:Alpha-1-antitrypsin deficiency (1)

Inborn genetic diseases (1)

not specified (1)

SERPINA1-related disorder (1)

Cystic fibrosis (1)

PI S (1)

Susceptibility to severe coronavirus disease (COVID-19) (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0055

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.6

PhyloP100

6.5

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.93

gMVP

0.74

Mutation Taster

=28/72

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over