rs5907

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_000185.4(SERPIND1):c.623G>A(p.Arg208His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,202 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

SERPIND1
NM_000185.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter P:1B:1

Conservation

PhyloP100: 10.0

Publications

26 publications found

Variant links:

Genes affected

SERPIND1 (HGNC:4838): (serpin family D member 1) This gene belongs to the serpin gene superfamily. Serpins play roles in many processes including inflammation, blood clotting, and cancer metastasis. Members of this family have highly conserved secondary structures with a reactive center loop that interacts with the protease active site to inhibit protease activity. This gene encodes a plasma serine protease that functions as a thrombin and chymotrypsin inhibitor. The protein is activated by heparin, dermatan sulfate, and glycosaminoglycans. Allelic variations in this gene are associated with heparin cofactor II deficiency. [provided by RefSeq, Jul 2015]

SERPIND1 links:

PI4KA (HGNC:8983): (phosphatidylinositol 4-kinase alpha) This gene encodes a phosphatidylinositol (PI) 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. The protein encoded by this gene is a type III enzyme that is not inhibited by adenosine. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2018]

PI4KA Gene-Disease associations (from GenCC):

polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

PI4KA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.050468773).

BP6

Variant 22-20779935-G-A is Benign according to our data. Variant chr22-20779935-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 14952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 236 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPIND1	NM_000185.4 link	c.623G>A	p.Arg208His	missense_variant	Exon 2 of 5	ENST00000215727.10	NP_000176.2	P05546Q8IVC0
PI4KA	NM_058004.4 link	c.2328+13258C>T		intron_variant	Intron 19 of 54	ENST00000255882.11	NP_477352.3	P42356-1Q4LE69B4DYG5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPIND1	ENST00000215727.10 link	c.623G>A	p.Arg208His	missense_variant	Exon 2 of 5	1	NM_000185.4	ENSP00000215727.5		P05546
PI4KA	ENST00000255882.11 link	c.2328+13258C>T		intron_variant	Intron 19 of 54	1	NM_058004.4	ENSP00000255882.6		P42356-1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00138

AC:

346

AN:

251386

AF XY:

0.00138

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00225

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00177

AC:

2593

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1236

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00286

AC:

153

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00211

AC:

2346

AN:

1112012

Other (OTH)

AF:

0.000977

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

151

302

453

604

755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.00155

AC:

236

AN:

152312

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41562

American (AMR)

AF:

0.000850

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00238

AC:

162

AN:

68040

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00188

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00131

AC:

159

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00172

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Heparin cofactor II deficiency

Pathogenic:1Benign:1

Mar 25, 1989

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.050

T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.029

D;D

Sift4G

Uncertain

0.045

D;D

Polyphen

0.98

D;D

Vest4

0.85

MVP

0.96

MPC

0.64

ClinPred

0.18

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.79

Mutation Taster

=6/94

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over