rs121909559

Variant names:

• chr1-173904038-C-G
• rs121909548
• NM_000488.4:c.1246G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-173904038-C-G
• chr1-173904038-C-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PP3 PP4 PP1_Strong PS4_Moderate PM5 PM1

This summary comes from the ClinGen Evidence Repository: The c.1246G>C variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by proline at amino acid 416 (p.Ala416Pro). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL and abnormal crossed electrophoresis, which is highly specific for autosomal dominant hereditary antithrombin deficiency (PP4, PMID:4082101). This variant has been reported in two more probands meeting an antithrombin activity level of < 0.8 IU/mL and a family history of disease with reported decreased antithrombin activity levels (PS4_Moderate; PMID:24583439, 2093312). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in at least 9 affected meioses from 4 families (PP1_Strong; PMID:33725558, 4082101, 24583439, 2093312).This variant resides within an reactive site residues (Ala416) of SERPINC1 that is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PM1). Another missense variant c.1246G>T (p.Ala416Ser) (ClinVarID:18023) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5).The computational predictor REVEL gives a score of 0.837, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic forautosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1_strong, PM1, PM5, PS4_moderate, PP3, PP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210750/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.22
• Publications: 47 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: Pathogenic. The variant received 13 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.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.1246G>C	p.Ala416Pro	missense	Exon 7 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1369G>C	p.Ala457Pro	missense	Exon 7 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1327G>C	p.Ala443Pro	missense	Exon 8 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.1246G>C	p.Ala416Pro	missense	Exon 7 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1375G>C	p.Ala459Pro	missense	Exon 7 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1369G>C	p.Ala457Pro	missense	Exon 7 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary antithrombin deficiency (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.88		Gain of glycosylation at A416 (P = 0.0201)
MVP		0.95
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97
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

Other links and lift over

dbSNP: rs121909548; hg19: chr1-173873176;