rs17473

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001085.5(SERPINA3):c.754C>G(p.Pro252Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,614,150 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 18 hom. )

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:4

Conservation

PhyloP100: 0.0920

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 14-94619305-C-G is Benign according to our data. Variant chr14-94619305-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 18050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94619305-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SERPINA3	NM_001085.5 linkuse as main transcript	c.754C>G	p.Pro252Ala	missense_variant	3/5	ENST00000393078.5	NP_001076.2
SERPINA3	NM_001384672.1 linkuse as main transcript	c.754C>G	p.Pro252Ala	missense_variant	3/5		NP_001371601.1
SERPINA3	NM_001384673.1 linkuse as main transcript	c.754C>G	p.Pro252Ala	missense_variant	4/6		NP_001371602.1
SERPINA3	NM_001384674.1 linkuse as main transcript	c.754C>G	p.Pro252Ala	missense_variant	4/6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA3	ENST00000393078.5 linkuse as main transcript	c.754C>G	p.Pro252Ala	missense_variant	3/5	1	NM_001085.5	ENSP00000376793	P1	P01011-1

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

468

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00576

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00286

AC:

718

AN:

251450

Hom.:

AF XY:

0.00282

AC XY:

383

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00572

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00472

AC:

6894

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

3278

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.00592

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.00307

AC:

468

AN:

152258

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000987

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00576

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00518

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00302

AC:

367

EpiCase

AF:

0.00431

EpiControl

AF:

0.00415

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SERPINA3: PP3, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ANTICHYMOTRYPSIN BONN 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 1993

- -

SERPINA3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Uncertain

0.54

D;D;.;D;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.82

T;.;T;.;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.5

L;L;.;L;.

MutationTaster

Benign

1.8e-8

A;A;A;A;A

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-5.6

D;D;D;D;D

REVEL

Uncertain

0.49

Sift

Benign

0.099

T;T;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T

Polyphen

0.027

B;B;.;B;.

Vest4

0.18

MVP

0.90

MPC

0.036

ClinPred

0.013

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.67

Position offset: 1

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