chr1-173904038-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM5PP2BP4_Moderate

The NM_001386302.1(SERPINC1):c.1369G>T(p.Ala457Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A457P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 1 hom. )

Consequence

SERPINC1
NM_001386302.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3B:2

Conservation

PhyloP100: 7.22

Publications

47 publications found

Variant links:

COSMIC-nc: COSV108207154

Genes affected

SERPINC1 (HGNC:775): (serpin family C member 1) The protein encoded by this gene, antithrombin III, is a plasma protease inhibitor and a member of the serpin superfamily. This protein inhibits thrombin as well as other activated serine proteases of the coagulation system, and it regulates the blood coagulation cascade. The protein includes two functional domains: the heparin binding-domain at the N-terminus of the mature protein, and the reactive site domain at the C-terminus. The inhibitory activity is enhanced by the presence of heparin. Numerous mutations have been identified for this gene, many of which are known to cause antithrombin-III deficiency which constitutes a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Sep 2020]

SERPINC1 Gene-Disease associations (from GenCC):

hereditary antithrombin deficiency
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen

SERPINC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-173904038-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 18007.Status of the report is reviewed_by_expert_panel, 3 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 1.3587 (below the threshold of 3.09). Trascript score misZ: 2.7782 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary antithrombin deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.2164593).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386302.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SERPINC1	NM_000488.4	MANE Select	c.1246G>T	p.Ala416Ser	missense	Exon 7 of 7	NP_000479.1
SERPINC1	NM_001386302.1		c.1369G>T	p.Ala457Ser	missense	Exon 7 of 7	NP_001373231.1
SERPINC1	NM_001386303.1		c.1327G>T	p.Ala443Ser	missense	Exon 8 of 8	NP_001373232.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SERPINC1	ENST00000367698.4	TSL:1 MANE Select	c.1246G>T	p.Ala416Ser	missense	Exon 7 of 7	ENSP00000356671.3
SERPINC1	ENST00000874328.1		c.1375G>T	p.Ala459Ser	missense	Exon 7 of 7	ENSP00000544387.1
SERPINC1	ENST00000874324.1		c.1369G>T	p.Ala457Ser	missense	Exon 7 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000887

AC:

223

AN:

251358

AF XY:

0.000832

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00149

AC:

2185

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1009

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.00163

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00181

AC:

2013

AN:

1112006

Other (OTH)

AF:

0.00146

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00109

AC:

166

AN:

152350

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41578

American (AMR)

AF:

0.00242

AC:

AN:

15308

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:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00168

AC:

114

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00144

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000717

AC:

EpiCase

AF:

0.00169

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary antithrombin deficiency (6)

not provided (2)

not specified (1)

Thrombocytopenia;C1458140:Abnormal bleeding (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.22

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.3

PhyloP100

7.2

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.59

MVP

0.86

MPC

1.1

ClinPred

0.15

GERP RS

5.7

Varity_R

0.85

gMVP

0.84

Mutation Taster

=37/63

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over