rs11558261

Positions:

chr14-94382823-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The ENST00000393087.9(SERPINA1):c.415G>A(p.Gly139Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,246 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 Pathogenic,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

SERPINA1
ENST00000393087.9 missense

Scores

Clinical Significance

Pathogenic; other no assertion criteria provided P:1O:4

Conservation

PhyloP100: 4.59

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant 14-94382823-C-T is Pathogenic according to our data. Variant chr14-94382823-C-T is described in ClinVar as [Pathogenic, other]. Clinvar id is 17986.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-94382823-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA1	NM_000295.5 linkuse as main transcript	c.415G>A	p.Gly139Ser	missense_variant	2/5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9 linkuse as main transcript	c.415G>A	p.Gly139Ser	missense_variant	2/5	1	NM_000295.5	ENSP00000376802	P1	P01009-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251382

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:1Other:4

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital

Dec 08, 2014

Reduced enzyme activity -

PI Q0(NEWPORT)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI NULL(NEWPORT)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI NULL(DEVON)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI Q0(DEVON)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;T;T;T;T;T;T;T;.;.;.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;M;M;M;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.3

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

REVEL

Pathogenic

0.67

Sift

Benign

0.075

T;T;T;T;T;.;T;T;T;T;T;T;T

Sift4G

Benign

0.23

T;T;T;T;T;.;T;T;T;T;.;.;.

Polyphen

1.0

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

Vest4

0.71

MutPred

0.83

Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);.;Gain of catalytic residue at G139 (P = 0.0022);Gain of catalytic residue at G139 (P = 0.0022);

MVP

1.0

MPC

0.30

ClinPred

0.89

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.70

gMVP

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over