dbSNP rs144060757: SERPINA3:p.Pro25Thr (chr14-94614514-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001085.5(SERPINA3):c.73C>A(p.Pro25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P25S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.316

Variant links:

Genes affected

SERPINA3 (HGNC:16): (serpin family A member 3) The protein encoded by this gene is a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. This gene is one in a cluster of serpin genes located on the q arm of chromosome 14. Polymorphisms in this protein appear to be tissue specific and influence protease targeting. Variations in this protein's sequence have been implicated in Alzheimer's disease, and deficiency of this protein has been associated with liver disease. Mutations have been identified in patients with Parkinson disease and chronic obstructive pulmonary disease. [provided by RefSeq, Jun 2020]

SERPINA3 links:

ENSG00000273259 (HGNC:):

ENSG00000273259 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
SERPINA3	NM_001085.5 link	c.73C>A	p.Pro25Thr	missense_variant	Exon 2 of 5	ENST00000393078.5	NP_001076.2	P01011-1A0A024R6P0
SERPINA3	NM_001384672.1 link	c.73C>A	p.Pro25Thr	missense_variant	Exon 2 of 5		NP_001371601.1
SERPINA3	NM_001384673.1 link	c.73C>A	p.Pro25Thr	missense_variant	Exon 3 of 6		NP_001371602.1
SERPINA3	NM_001384674.1 link	c.73C>A	p.Pro25Thr	missense_variant	Exon 3 of 6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINA3	ENST00000393078.5 link	c.73C>A	p.Pro25Thr	missense_variant	Exon 2 of 5	1	NM_001085.5	ENSP00000376793.3	P01011-1
ENSG00000273259	ENST00000553947.1 link	n.*899C>A		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000452367.2	G3V5I3
ENSG00000273259	ENST00000553947.1 link	n.*899C>A		3_prime_UTR_variant	Exon 5 of 8	2		ENSP00000452367.2	G3V5I3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D;.;D

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.43

T;.;T;.

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.3

M;M;.;M

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-5.2

D;D;D;D

REVEL

Uncertain

0.35

Sift

Benign

0.062

T;T;D;T

Sift4G

Uncertain

0.023

D;D;D;D

Polyphen

0.86

P;P;.;P

Vest4

0.21

MutPred

0.42

Gain of catalytic residue at P25 (P = 0);Gain of catalytic residue at P25 (P = 0);Gain of catalytic residue at P25 (P = 0);Gain of catalytic residue at P25 (P = 0);

MVP

0.92

MPC

0.040

ClinPred

0.93

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.11

gMVP

0.14

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over