rs121909556

Variant names:

• chr1-173904010-C-T
• rs121909549
• NM_000488.4:c.1274G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-173904010-C-T
• chr1-173904010-C-G

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PP3 PP4 PS4 PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1274G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 425 (p.Arg425His; legacy nomenclature p.R393H aka Antithrombin Glasgow). The computational predictor REVEL gives a score of 0.806, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant is at extremely low frequency (Total: 0.000003979, European (non-Finnish): 0.000008798) in gnomAD v2.1.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting (MAF <2.0 X 10-5). This variant has been reported in at least 16 probands in the literature with AT deficiency meeting PP4 and PS4_VeryStrong (PMID:26134363; 27766527; 28607330; 28300866; 3179448). Additionally, this variant has been report in at least 4 meioses across 14 families meeting PP1_Moderate. In summary, based on the evidence available at this time, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Moderate, PP3, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210766/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.22
• Publications: 5 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

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

Our verdict: Pathogenic. The variant received 9 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	NM_000488.4	MANE Select	c.1274G>A	p.Arg425His	missense	Exon 7 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1397G>A	p.Arg466His	missense	Exon 7 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1355G>A	p.Arg452His	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.1274G>A	p.Arg425His	missense	Exon 7 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1403G>A	p.Arg468His	missense	Exon 7 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1397G>A	p.Arg466His	missense	Exon 7 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251350 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary antithrombin deficiency (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.81
Sift	Benign	0.28	T
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.86		Loss of methylation at R425 (P = 0.0245)
MVP		0.85
MPC		1.3
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.85
Mutation Taster		=6/94	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: rs121909549; hg19: chr1-173873148;