Genetic Variant SERPINA9:p.Pro218Leu (chr14-94467358-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_175739.4(SERPINA9):c.653C>T(p.Pro218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,610,776 control chromosomes in the GnomAD database, including 78,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6444 hom., cov: 33)

Exomes 𝑓: 0.31 ( 72152 hom. )

Consequence

SERPINA9
NM_175739.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.581

Publications

25 publications found

Variant links:

Genes affected

SERPINA9 (HGNC:15995): (serpin family A member 9) Enables serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in cytoplasm and membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SERPINA9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00118348).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA9	NM_175739.4 link	c.653C>T	p.Pro218Leu	missense_variant	Exon 3 of 5	ENST00000674397.2	NP_783866.3	Q86WD7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA9	ENST00000674397.2 link	c.653C>T	p.Pro218Leu	missense_variant	Exon 3 of 5		NM_175739.4	ENSP00000501517.1		Q86WD7-1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42785

AN:

152048

Hom.:

6440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.359

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.433

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.339

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.296

GnomAD2 exomes

AF:

0.319

AC:

79139

AN:

248242

AF XY:

0.320

show subpopulations

Gnomad AFR exome

AF:

0.163

Gnomad AMR exome

AF:

0.357

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.440

Gnomad FIN exome

AF:

0.319

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.316

GnomAD4 exome

AF:

0.312

AC:

455417

AN:

1458610

Hom.:

72152

Cov.:

AF XY:

0.314

AC XY:

227356

AN XY:

724890

show subpopulations

African (AFR)

AF:

0.163

AC:

5447

AN:

33408

American (AMR)

AF:

0.362

AC:

16174

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

8009

AN:

26110

East Asian (EAS)

AF:

0.452

AC:

17885

AN:

39608

South Asian (SAS)

AF:

0.352

AC:

30310

AN:

86082

European-Finnish (FIN)

AF:

0.323

AC:

17224

AN:

53346

Middle Eastern (MID)

AF:

0.232

AC:

1334

AN:

5758

European-Non Finnish (NFE)

AF:

0.307

AC:

340110

AN:

1109472

Other (OTH)

AF:

0.314

AC:

18924

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

16699

33397

50096

66794

83493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11318

22636

33954

45272

56590

<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

AF:

0.281

AC:

42817

AN:

152166

Hom.:

6444

Cov.:

AF XY:

0.285

AC XY:

21230

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.174

AC:

7222

AN:

41530

American (AMR)

AF:

0.359

AC:

5490

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1036

AN:

3470

East Asian (EAS)

AF:

0.433

AC:

2233

AN:

5154

South Asian (SAS)

AF:

0.371

AC:

1791

AN:

4826

European-Finnish (FIN)

AF:

0.339

AC:

3598

AN:

10598

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.301

AC:

20438

AN:

67990

Other (OTH)

AF:

0.303

AC:

639

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1611

3222

4833

6444

8055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

432

864

1296

1728

2160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.296

Hom.:

22130

Bravo

AF:

0.275

TwinsUK

AF:

0.307

AC:

1140

ALSPAC

AF:

0.319

AC:

1230

ESP6500AA

AF:

0.162

AC:

622

ESP6500EA

AF:

0.301

AC:

2486

ExAC

AF:

0.314

AC:

37964

Asia WGS

AF:

0.414

AC:

1440

AN:

3478

EpiCase

AF:

0.301

EpiControl

AF:

0.299

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.16

.;.;.;.;T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.69

T;T;T;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;.;.;.;M;.

PhyloP100

0.58

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-6.2

D;D;D;D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.011

D;T;D;D;T;D

Sift4G

Benign

0.17

T;T;T;T;T;T

Polyphen

0.39

B;P;.;B;B;B

Vest4

0.18

MPC

0.019

ClinPred

0.034

GERP RS

1.9

Varity_R

0.19

gMVP

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over