rs121909550

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. PM2_SupportingPP3PP4PP1_StrongPS4PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000488.4(SERPINC1):c.1277C>T variant predicts a missense change from Serine to Leucine at position 426. Several probands and related individuals are reported in the literature with antithrombin deficiency and the Ser426Leu variant, meeting criteria for PS4 and PP4 (PMID:34800304, 36093136, 3563966, 28300866, 30721820). The variant was seen across a total of 8 meioses amongst 3 families meeting PP1_Strong (PMID:30721820, 3512602, 3563966). The variant was shown to impair complex formation with thrombin when the variant was expressed in rabbit reticulocytes (PMID:2207328). The variant is absent in gnomAD (v2.1.1 and v3.1.1) meeting PM2_Supporting. It has a REVEL score of 0.88, which meets the PP3 set threshold (>0.6). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel: PS4, PP1_Strong, PP3, PP4, PS3_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210754/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

10

6

2

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 9.14

Publications

11 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: 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: Pathogenic. The variant received 12 ACMG points.

PS3

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

PS4

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

PM2

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	NM_000488.4	MANE Select	c.1277C>T	p.Ser426Leu	missense	Exon 7 of 7	NP_000479.1
	SERPINC1	NM_001386302.1		c.1400C>T	p.Ser467Leu	missense	Exon 7 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1358C>T	p.Ser453Leu	missense	Exon 8 of 8	NP_001373232.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	ENST00000367698.4	TSL:1 MANE Select	c.1277C>T	p.Ser426Leu	missense	Exon 7 of 7	ENSP00000356671.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152164

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461860

Hom.:

0

Cov.:

31

AF XY:

0.00

AC XY:

0

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33480

American (AMR)

AF:

0.00

AC:

0

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:

0.00

AC:

0

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

1

AN:

1111988

Other (OTH)

AF:

0.00

AC:

0

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152164

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74340

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

1

AN:

41434

American (AMR)

AF:

0.00

AC:

0

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

68034

Other (OTH)

AF:

0.00

AC:

0

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

0

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

3

-

-

Hereditary antithrombin deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.40

D

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.94

D

M_CAP

Uncertain

0.16

D

MetaRNN

Pathogenic

0.92

D

MetaSVM

Uncertain

0.39

D

MutationAssessor

Pathogenic

3.0

M

PhyloP100

9.1

PrimateAI

Uncertain

0.53

T

PROVEAN

Uncertain

-3.8

D

REVEL

Pathogenic

0.88

Sift

Benign

0.039

D

Sift4G

Uncertain

0.0060

D

Polyphen

1.0

D

Vest4

0.95

MVP

0.94

MPC

1.1

ClinPred

1.0

D

GERP RS

5.7

Varity_R

0.94

gMVP

0.91

Mutation Taster

=2/98

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs121909550; hg19: chr1-173873145; COSMIC: COSV62928911; COSMIC: COSV62928911; API