rs121909552

Variant names:

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.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant is an established founder variant known as AT Padua I making it ineligible for the BS1 rule application. It has a REVEL score of 0.702, and meets PP3. At least 23 individuals with AT deficiency meeting the SERPINC1 phenotype criteria (other cases are reported but do not meet criteria) are reported in the literature meeting PS4_Very Strong and PP4. Additionally, 9 meioses have been reported across 16 families meeting PP1_Strong. In summary, this variant reaches a classification of pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Strong, PM1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210758/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

3

13

2

Clinical Significance

Pathogenic reviewed by expert panel P:13U:1B:1

Conservation

PhyloP100: 5.83

Publications

18 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.236G>A	p.Arg79His	missense	Exon 2 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.236G>A	p.Arg79His	missense	Exon 2 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.317G>A	p.Arg106His	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.236G>A	p.Arg79His	missense	Exon 2 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.236G>A	p.Arg79His	missense	Exon 2 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.236G>A	p.Arg79His	missense	Exon 2 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

27

AN:

152228

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000954

AC:

24

AN:

251464

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000231

AC:

337

AN:

1461882

Hom.:

0

Cov.:

31

AF XY:

0.000246

AC XY:

179

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000597

AC:

2

AN:

33480

American (AMR)

AF:

0.0000224

AC:

1

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

5

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

1

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

2

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

3

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5764

European-Non Finnish (NFE)

AF:

0.000281

AC:

313

AN:

1112008

Other (OTH)

AF:

0.000166

AC:

10

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0

20

40

60

80

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

20

40

60

80

100

<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:

0.000177

AC:

27

AN:

152346

Hom.:

0

Cov.:

32

AF XY:

0.000161

AC XY:

12

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000721

AC:

3

AN:

41582

American (AMR)

AF:

0.00

AC:

0

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

1

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

23

AN:

68036

Other (OTH)

AF:

0.00

AC:

0

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0

2

3

5

6

8

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:

0.000349

Hom.:

0

Bravo

AF:

0.000208

ESP6500AA

AF:

0.000454

AC:

2

ESP6500EA

AF:

0.000233

AC:

2

ExAC

AF:

0.0000494

AC:

6

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

9

1

1

Hereditary antithrombin deficiency (11)

3

-

-

not provided (3)

1

-

-

SERPINC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.13

D

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

26

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Uncertain

0.94

D

M_CAP

Uncertain

0.086

D

MetaRNN

Benign

0.38

T

MetaSVM

Uncertain

0.086

D

MutationAssessor

Uncertain

2.2

M

PhyloP100

5.8

PrimateAI

Uncertain

0.69

T

PROVEAN

Benign

-1.5

N

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

D

Sift4G

Uncertain

0.017

D

Polyphen

0.98

D

Vest4

0.67

MVP

0.94

MPC

0.79

ClinPred

0.19

T

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.81

Mutation Taster

=6/94

disease causing (ClinVar)

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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Other links and lift over

dbSNP: rs121909552; hg19: chr1-173883863; COSMIC: COSV62930719; COSMIC: COSV62930719; API