dbSNP rs772436715: SERPINA1:p.Asp294Tyr (chr14-94380908-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000295.5(SERPINA1):c.880G>T(p.Asp294Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D294N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0470

Publications

0 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, 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5 link	c.880G>T	p.Asp294Tyr	missense_variant	Exon 3 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9 link	c.880G>T	p.Asp294Tyr	missense_variant	Exon 3 of 5	1	NM_000295.5	ENSP00000376802.4		P01009-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

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

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.46

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

M_CAP

Benign

0.077

MetaRNN

Uncertain

0.50

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.5

M;M;M;M;M;M;M;M;M;M

PhyloP100

0.047

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.6

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

REVEL

Benign

0.24

Sift

Uncertain

0.0070

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

Sift4G

Uncertain

0.010

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

Polyphen

0.99

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

Vest4

0.28

MutPred

0.54

Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);Gain of catalytic residue at E290 (P = 0.0024);

MVP

0.95

MPC

0.29

ClinPred

0.91

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.54

Mutation Taster

=78/22

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over