NM_000488.4:c.529C>T

Variant names:

• chr1-173911894-G-A
• rs143521873
• NM_000488.4:c.529C>T
• SERPINC1 p.Arg177Cys

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. PP3 BS1

This summary comes from the ClinGen Evidence Repository: The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002. One proband in PMID:28300866 and three probands from internal data with AT deficiency are noted to carry the variant ; however PS4 is not applied since BS1 is met. The variant has a REVEL score of 0.873, which exceeds the cutoff (>0.6) set by the VCEP. Thrombosis VCEP considers this variant as a variant of uncertain significance due to the presence of at least 4 cases with AT deficiency and a high REVEL score. While the population frequency is high, the absence of homozygotes in the population may argue against the variant being benign. The experimental evidence is unreliable with varying activity levels on different assays. A conservative approach would be to classify this variant as uncertain. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1251403/MONDO:0013144/084

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 9.60
• Publications: 3 publications found

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

ACMG classification

Specifications for SERPINC1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received -3 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.529C>T	p.Arg177Cys	missense	Exon 3 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.529C>T	p.Arg177Cys	missense	Exon 3 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.610C>T	p.Arg204Cys	missense	Exon 4 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.529C>T	p.Arg177Cys	missense	Exon 3 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.529C>T	p.Arg177Cys	missense	Exon 3 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.529C>T	p.Arg177Cys	missense	Exon 3 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251482 AF XY: 0.000103

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727240

African (AFR) AF: 0.00170 AC: 57 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111986

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

GnomAD4 genome AF: 0.000539 AC: 82 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74352

African (AFR) AF: 0.00188 AC: 78 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000518

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary antithrombin deficiency (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Varity_R		0.76
gMVP		0.93
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs143521873;

hg19: chr1-173881032;

COSMIC: COSV104424404;

COSMIC: COSV104424404;