dbSNP rs28929470: SERPINA1:p.Arg247Cys (chr14-94381049-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP5BP4BS1_SupportingBS2_Supporting

The NM_000295.5(SERPINA1):c.739C>T(p.Arg247Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,614,004 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign 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. R247H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 5 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:8O:1

Conservation

PhyloP100: 2.29

Publications

38 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: Likely_benign. The variant received -2 ACMG points.

PP5

Variant 14-94381049-G-A is Pathogenic according to our data. Variant chr14-94381049-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17961.

BP4

Computational evidence support a benign effect (MetaRNN=0.029084444). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00197 (299/152138) while in subpopulation NFE AF = 0.00362 (246/67998). AF 95% confidence interval is 0.00325. There are 1 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 5 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.739C>T	p.Arg247Cys	missense	Exon 3 of 5	NP_000286.3
SERPINA1	NM_001002235.3		c.739C>T	p.Arg247Cys	missense	Exon 3 of 5	NP_001002235.1	E9KL23
SERPINA1	NM_001002236.3		c.739C>T	p.Arg247Cys	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.739C>T	p.Arg247Cys	missense	Exon 3 of 5	ENSP00000376802.4	P01009-1
SERPINA1	ENST00000355814.8	TSL:1	c.739C>T	p.Arg247Cys	missense	Exon 3 of 5	ENSP00000348068.4	P01009-1
SERPINA1	ENST00000393088.8	TSL:1	c.739C>T	p.Arg247Cys	missense	Exon 5 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

300

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00212

AC:

533

AN:

251358

AF XY:

0.00214

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00428

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00319

AC:

4658

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2255

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00404

AC:

4495

AN:

1111992

Other (OTH)

AF:

0.00162

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

234

468

702

936

1170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.00197

AC:

299

AN:

152138

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41514

American (AMR)

AF:

0.000392

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00362

AC:

246

AN:

67998

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00305

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00287

AC:

349

EpiCase

AF:

0.00278

EpiControl

AF:

0.00279

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha-1-antitrypsin deficiency (7)

not provided (3)

Inborn genetic diseases (1)

not specified (1)

SERPINA1-related disorder (1)

PI F (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

0.0064

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.016

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.029

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.7

PhyloP100

2.3

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-6.7

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.86

MVP

0.93

MPC

0.17

ClinPred

0.13

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.51

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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