NM_000488.4:c.391C>G

Variant names:

• chr1-173914570-G-C
• rs121909567
• NM_000488.4:c.391C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2_Supporting PP4 PP3 PM5

This summary comes from the ClinGen Evidence Repository: The NM_000488.4:c.391C>G variant in SERPINC1 is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 131 (p.Leu131Val). This variant is also known as antithrombin Southport (Legacy nomenclature: Leu99Val) in the literature. One proband from PMID:7734360 with AT deficiency (type II-HBS) meets criteria for PP4. At least one patient with this variant displayed AT deficiency (type II- HBS) which is highly specific for SERPINC1 (PP4, PMID:7734360). Another missense variant, c.391C>T (p.Leu131Phe), in the same codon has been classified as pathogenic for antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.764, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 gene function (PP3). This variant is absent from gnomAD v2.1.1-v4. In summary, this variant meets the criteria to be classified as a variant of uncertain significance forantithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP. (Specifications version 1.0.0; date of approval: 7/17/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA343777244/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 9.60
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.391C>G	p.Leu131Val	missense	Exon 2 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.391C>G	p.Leu131Val	missense	Exon 2 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.472C>G	p.Leu158Val	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.391C>G	p.Leu131Val	missense	Exon 2 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.391C>G	p.Leu131Val	missense	Exon 2 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.391C>G	p.Leu131Val	missense	Exon 2 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary antithrombin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.57	N
REVEL	Pathogenic	0.76
Sift	Benign	0.30	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.66		Gain of catalytic residue at L131 (P = 0.0046)
MVP		0.94
MPC		1.1
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.65
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs121909567; hg19: chr1-173883708;