dbSNP rs61761869: SERPINA1:p.Pro393Ser (chr14-94378529-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PM5PP3_StrongPP5_Very_Strong

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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000630387: Experimental studies have shown that this missense change affects SERPINA1 function (PMID:10234508, 27296815)." and additional evidence is available in ClinVar. 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1

Conservation

PhyloP100: 8.72

Publications

33 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, PanelApp Australia, 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: Pathogenic. The variant received 18 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000630387: Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508, 27296815).; SCV000711354: "In vitro and in vivo functional studies provide some evidence that the p.Pro393Ser variant may impact protein function; however, these types of assays may not accurately represent biological function (Poller 1999, Fra 2012)."; SCV000915659: 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. PMID:10495076; SCV002768009: In vitro and in vivo functional studies have demonstrated that this variant results in intracellular transportation and secretion defects (PMID: 10234508; 22723858); SCV005884918: The variant results in a complete intracellular transport block in cell cultures in vitro (Poller_1999). PMID:18024524

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-94378529-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219360.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 289135.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA1	NM_000295.5	MANE Select	c.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	NP_000286.3
SERPINA1	NM_001002235.3		c.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	NP_001002235.1	E9KL23
SERPINA1	NM_001002236.3		c.1177C>T	p.Pro393Ser	missense	Exon 7 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.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	ENSP00000376802.4	P01009-1
SERPINA1	ENST00000355814.8	TSL:1	c.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	ENSP00000348068.4	P01009-1
SERPINA1	ENST00000393088.8	TSL:1	c.1177C>T	p.Pro393Ser	missense	Exon 7 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000290

AC:

AN:

251474

AF XY:

0.000353

show subpopulations

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 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.:

Cov.:

AF XY:

0.000385

AC XY:

280

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000433

AC:

481

AN:

1111998

Other (OTH)

AF:

0.000447

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

118

147

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:

0.000315

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41542

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000550

Hom.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha-1-antitrypsin deficiency (10)

not provided (4)

SERPINA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.58

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

8.7

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.033

Polyphen

1.0

Vest4

0.83

MVP

1.0

MPC

0.31

ClinPred

0.96

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.63

gMVP

0.77

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over