rs199422213

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000295.5(SERPINA1):c.326C>T(p.Thr109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,824 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T109T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2O:1

Conservation

PhyloP100: 2.24

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5 linkuse as main transcript	c.326C>T	p.Thr109Met	missense_variant	2/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9 linkuse as main transcript	c.326C>T	p.Thr109Met	missense_variant	2/5	1	NM_000295.5	P1	P01009-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251266

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1460476

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726274

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000752

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 24, 2022	- -
Likely pathogenic, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 04, 2018

- -

PI Z(BRISTOL)

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

0.13

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.10

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.43

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

Eigen

Benign

0.10

Eigen_PC

Benign

-0.071

FATHMM_MKL

Benign

0.58

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.87

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

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.6

H;H;H;H;H;H;H;H;H;H;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.3

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

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.98

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

Vest4

0.83

MutPred

0.76

Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);.;Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);Loss of glycosylation at T109 (P = 0.054);

MVP

0.97

MPC

0.29

ClinPred

0.98

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.50

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