chr1-173904044-C-T

Variant names:

• chr1-173904044-C-T
• rs121909557
• NM_000488.4:c.1240G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2_Supporting PP3 PP4 PP1 PS4_Moderate PM1

This summary comes from the ClinGen Evidence Repository: The c.1240G>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 414 (p.Ala414Thr). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:36764659). This variant has been reported in 4 more probands meeting an antithrombin activity level of < 0.8 IU/mL on repeated independent tests or a family history of disease with reported antithrombin levels (PS4_Moderate, 3.5pts; PMID:25466846, 24684277, 3179438, 28300866). One proband did not meet the full requirements and thus half a point is awarded. The variant has been reported to segregate with hereditary antithrombin deficiency in at least 2 additional affected family members from one family (PP1; PMID:3179438).This variant resides within a residue, Ala414, of SERPINC1 that is defined as a reactive site residue by the ClinGen Thrombosis VCEP (PMID:2615648, PM1). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 (4/1180010 alleles) in European (non-Finnish) population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002) for PM2_Supporting, meeting this criterion (PM2_Supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM1, PS4_moderate, PP1, PP3, PP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210768/MONDO:0013144/084

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.22
• Publications: 2 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: Likely_pathogenic. The variant received 8 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.
• 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.1240G>A	p.Ala414Thr	missense	Exon 7 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1363G>A	p.Ala455Thr	missense	Exon 7 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1321G>A	p.Ala441Thr	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.1240G>A	p.Ala414Thr	missense	Exon 7 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1369G>A	p.Ala457Thr	missense	Exon 7 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1363G>A	p.Ala455Thr	missense	Exon 7 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely 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	0.78
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.87		Gain of phosphorylation at A414 (P = 0.0213)
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.93
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: rs121909557; hg19: chr1-173873182;