dbSNP rs17473: SERPINA3:p.Pro252Thr (chr14-94619305-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_001085.5(SERPINA3):c.754C>A(p.Pro252Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 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. P252A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0920

Publications

0 publications found

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 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
SERPINA3	NM_001085.5 link	c.754C>A	p.Pro252Thr	missense_variant	Exon 3 of 5	ENST00000393078.5	NP_001076.2	P01011-1A0A024R6P0
SERPINA3	NM_001384672.1 link	c.754C>A	p.Pro252Thr	missense_variant	Exon 3 of 5		NP_001371601.1
SERPINA3	NM_001384673.1 link	c.754C>A	p.Pro252Thr	missense_variant	Exon 4 of 6		NP_001371602.1
SERPINA3	NM_001384674.1 link	c.754C>A	p.Pro252Thr	missense_variant	Exon 4 of 6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINA3	ENST00000393078.5 link	c.754C>A	p.Pro252Thr	missense_variant	Exon 3 of 5	1	NM_001085.5	ENSP00000376793.3	P01011-1
ENSG00000273259	ENST00000553947.1 link	n.*1580C>A		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000452367.2	G3V5I3
ENSG00000273259	ENST00000553947.1 link	n.*1580C>A		3_prime_UTR_variant	Exon 6 of 8	2		ENSP00000452367.2	G3V5I3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000299

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:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;D;.;D;T

Eigen

Benign

-0.086

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.82

T;.;T;.;T

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.52

D;D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.7

M;M;.;M;.

PhyloP100

0.092

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.7

D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.058

T;T;T;T;D

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.88

P;P;.;P;.

Vest4

0.33

MutPred

0.49

Gain of catalytic residue at F254 (P = 0.0017);Gain of catalytic residue at F254 (P = 0.0017);Gain of catalytic residue at F254 (P = 0.0017);Gain of catalytic residue at F254 (P = 0.0017);.;

MVP

0.90

MPC

0.071

ClinPred

0.68

GERP RS

3.8

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.61

gMVP

0.42

Mutation Taster

=74/26

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over