rs121909570

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PM2PM5PP2BP4

The NM_000488.4(SERPINC1):c.500A>G(p.Asn167Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N167T) has been classified as Pathogenic.

Frequency

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

Consequence

SERPINC1
NM_000488.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

Publications

7 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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity ANT3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-173911923-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 18041.Status of the report is no_assertion_criteria_provided, 0 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: 2.7609 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary antithrombin deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.2958014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4 link	c.500A>G	p.Asn167Ser	missense_variant	Exon 3 of 7	ENST00000367698.4	NP_000479.1	P01008A0A024R944

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINC1	ENST00000367698.4 link	c.500A>G	p.Asn167Ser	missense_variant	Exon 3 of 7	1	NM_000488.4	ENSP00000356671.3	P01008
SERPINC1	ENST00000487183.1 link	n.205A>G		non_coding_transcript_exon_variant	Exon 2 of 4	2
SERPINC1	ENST00000494024.1 link	n.*57A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

.;D

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.2

.;L

PhyloP100

7.7

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

.;N

REVEL

Uncertain

0.31

Sift

Benign

0.046

.;D

Sift4G

Benign

0.35

T;T

Polyphen

0.041

.;B

Vest4

0.39

MutPred

0.50

Gain of phosphorylation at N167 (P = 0.0235);Gain of phosphorylation at N167 (P = 0.0235);

MVP

0.81

MPC

0.31

ClinPred

0.66

GERP RS

5.7

Varity_R

0.64

gMVP

0.40

Mutation Taster

=75/25

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over