dbSNP rs28931570: SERPINA1:p.Arg63Cys (chr14-94383051-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PS3PP5_Very_StrongBP4BS2_Supporting

The NM_000295.5(SERPINA1):c.187C>T(p.Arg63Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,613,714 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000389660: Mahadeva et al. (1999) performed an in vitro functional study and discovered the p.Arg63Cys variant protein is conformationally unstable and forms polymer chains, while the wild type SERPINA1 protein remains monomeric." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 7 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 2.88

Publications

37 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 10 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000389660: Mahadeva et al. (1999) performed an in vitro functional study and discovered the p.Arg63Cys variant protein is conformationally unstable and forms polymer chains, while the wild type SERPINA1 protein remains monomeric.; SCV000956623: Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10194472).; SCV003844885: Experimental evidence evaluating an impact on protein function demonstrated the variant exhibits decreased stability, and forms aberrant disulphide bonds leading to reduced secretion of a1-antitrypsin (Mahadeva_1999, Jung_2004, Ronzoni_2016).; SCV000521230: Published functional studies demonstrate that the R63C variant impairs protein secretion by forming aberrant disulfide bonds (Ronzoni et al., 2016); PMID:24713750

PP5

Variant 14-94383051-G-A is Pathogenic according to our data. Variant chr14-94383051-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.11158815). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.187C>T	p.Arg63Cys	missense	Exon 2 of 5	NP_000286.3
SERPINA1	NM_001002235.3		c.187C>T	p.Arg63Cys	missense	Exon 2 of 5	NP_001002235.1	E9KL23
SERPINA1	NM_001002236.3		c.187C>T	p.Arg63Cys	missense	Exon 4 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.187C>T	p.Arg63Cys	missense	Exon 2 of 5	ENSP00000376802.4	P01009-1
SERPINA1	ENST00000355814.8	TSL:1	c.187C>T	p.Arg63Cys	missense	Exon 2 of 5	ENSP00000348068.4	P01009-1
SERPINA1	ENST00000393088.8	TSL:1	c.187C>T	p.Arg63Cys	missense	Exon 4 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00272

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00106

AC:

266

AN:

251314

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00182

AC:

2653

AN:

1461366

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1246

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33470

American (AMR)

AF:

0.000492

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00225

AC:

2497

AN:

1111550

Other (OTH)

AF:

0.00174

AC:

105

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

181

362

544

725

906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00150

AC:

228

AN:

152348

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41578

American (AMR)

AF:

0.000915

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00272

AC:

185

AN:

68036

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00173

Hom.:

Bravo

AF:

0.00154

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.000972

AC:

118

EpiCase

AF:

0.00267

EpiControl

AF:

0.00302

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 (11)

not provided (3)

SERPINA1-related disorder (1)

PI I (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.3

PhyloP100

2.9

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.84

MVP

1.0

MPC

0.20

ClinPred

0.092

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.40

gMVP

0.59

Mutation Taster

=44/56

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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