rs121909551

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3PP4PP1_StrongPS4PM1

This summary comes from the ClinGen Evidence Repository: The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold for PM2_Supporting. At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong and PP4. There at least 17 meioses out of 35 families meeting PP1_Strong (PMID:28300866). This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3, and is within a heparin binding site, meeting PM1. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_VeryStrong, PP1_Strong, PM1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210756/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

6

9

3

Clinical Significance

Pathogenic reviewed by expert panel P:16U:1B:1

Conservation

PhyloP100: 9.42

Publications

27 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Orphanet, ClinGen

SERPINC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000488.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	NM_000488.4	MANE Select	c.218C>T	p.Pro73Leu	missense	Exon 2 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.218C>T	p.Pro73Leu	missense	Exon 2 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.299C>T	p.Pro100Leu	missense	Exon 3 of 8	NP_001373232.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	ENST00000367698.4	TSL:1 MANE Select	c.218C>T	p.Pro73Leu	missense	Exon 2 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.218C>T	p.Pro73Leu	missense	Exon 2 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.218C>T	p.Pro73Leu	missense	Exon 2 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152196

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000819

AC:

206

AN:

251456

AF XY:

0.000765

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00101

AC:

1470

AN:

1461878

Hom.:

3

Cov.:

31

AF XY:

0.000949

AC XY:

690

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000179

AC:

6

AN:

33480

American (AMR)

AF:

0.0000894

AC:

4

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

4

AN:

86258

European-Finnish (FIN)

AF:

0.00380

AC:

203

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5756

European-Non Finnish (NFE)

AF:

0.00110

AC:

1224

AN:

1112010

Other (OTH)

AF:

0.000480

AC:

29

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0

92

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

0

50

100

150

200

250

<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:

0.000840

AC:

128

AN:

152314

Hom.:

0

Cov.:

32

AF XY:

0.00102

AC XY:

76

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000241

AC:

10

AN:

41560

American (AMR)

AF:

0.00

AC:

0

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4830

European-Finnish (FIN)

AF:

0.00546

AC:

58

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

57

AN:

68030

Other (OTH)

AF:

0.00142

AC:

3

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0

8

17

25

34

42

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

0

2

4

6

8

10

<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:

0.000706

Hom.:

1

Bravo

AF:

0.000434

TwinsUK

AF:

0.00216

AC:

8

ALSPAC

AF:

0.000778

AC:

3

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.000465

AC:

4

ExAC

AF:

0.000717

AC:

87

EpiCase

AF:

0.000981

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

12

1

1

Hereditary antithrombin deficiency (14)

4

-

-

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.074

D

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

30

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.89

D

M_CAP

Benign

0.061

D

MetaRNN

Benign

0.044

T

MetaSVM

Uncertain

-0.24

T

MutationAssessor

Uncertain

2.2

M

PhyloP100

9.4

PrimateAI

Uncertain

0.60

T

PROVEAN

Uncertain

-3.5

D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

D

Sift4G

Uncertain

0.0050

D

Polyphen

1.0

D

Vest4

0.92

MVP

0.96

MPC

1.1

ClinPred

0.089

T

GERP RS

5.7

Varity_R

0.50

gMVP

0.85

Mutation Taster

=15/85

disease causing (ClinVar)

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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Other links and lift over

dbSNP: rs121909551; hg19: chr1-173883881; COSMIC: COSV104674878; COSMIC: COSV104674878; API