Genetic Variant SERPIND1:p.Asp77Asp (chr22-20779543-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000185.4(SERPIND1):c.231C>T(p.Asp77Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,613,928 control chromosomes in the GnomAD database, including 1,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 196 hom., cov: 32)

Exomes 𝑓: 0.0091 ( 1442 hom. )

Consequence

SERPIND1
NM_000185.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.11

Publications

12 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 Submitted by: G2P, Labcorp Genetics (formerly Invitae)

PI4KA links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 22-20779543-C-T is Benign according to our data. Variant chr22-20779543-C-T is described in ClinVar as Benign. ClinVar VariationId is 1268540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.11 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000185.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPIND1	NM_000185.4	MANE Select	c.231C>T	p.Asp77Asp	synonymous	Exon 2 of 5	NP_000176.2	P05546-1
PI4KA	NM_058004.4	MANE Select	c.2328+13650G>A		intron	N/A	NP_477352.3	P42356-1
PI4KA	NM_001362863.2		c.2262+13650G>A		intron	N/A	NP_001349792.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPIND1	ENST00000215727.10	TSL:1 MANE Select	c.231C>T	p.Asp77Asp	synonymous	Exon 2 of 5	ENSP00000215727.5	P05546-1
SERPIND1	ENST00000406799.1	TSL:1	c.231C>T	p.Asp77Asp	synonymous	Exon 1 of 4	ENSP00000384050.1	P05546-1
PI4KA	ENST00000255882.11	TSL:1 MANE Select	c.2328+13650G>A		intron	N/A	ENSP00000255882.6	P42356-1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2410

AN:

152198

Hom.:

185

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0639

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0388

AC:

9735

AN:

251058

AF XY:

0.0296

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0665

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.0281

GnomAD4 exome

AF:

0.00910

AC:

13301

AN:

1461612

Hom.:

1442

Cov.:

AF XY:

0.00780

AC XY:

5673

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33476

American (AMR)

AF:

0.225

AC:

10034

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0565

AC:

2242

AN:

39686

South Asian (SAS)

AF:

0.000962

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000174

AC:

194

AN:

1111818

Other (OTH)

AF:

0.0107

AC:

648

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

643

1285

1928

2570

3213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.0160

AC:

2437

AN:

152316

Hom.:

196

Cov.:

AF XY:

0.0170

AC XY:

1263

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00289

AC:

120

AN:

41570

American (AMR)

AF:

0.123

AC:

1876

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0638

AC:

331

AN:

5186

South Asian (SAS)

AF:

0.00187

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68032

Other (OTH)

AF:

0.0223

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00216

Hom.:

Bravo

AF:

0.0274

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.37

(source)

DANN

Benign

0.90

PhyloP100

-2.1

PromoterAI

0.0097

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=86/14

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over