chr1-173914872-A-T

Variant names:

• chr1-173914872-A-T
• rs2227624
• NM_000488.4:c.89T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PS4 PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.89T>A (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 30 (p.Val30Glu; legacy p.V-3E; also known as the founder variant antithrombin Dublin), so the BS1 code is excluded. This sequence variant has been previously reported in patients with transient antithrombin deficiency, who present with a history of reduced antithrombin activity with at least one reported normal antithrombin activity level (PMID:27975105; PMID:27098529; PMID:34800304) meeting PS4_Very Strong. Large cohort analysis demonstrate carriers of this variant have a 2.3-fold increased risk of thrombosis compared to the general population (PMID:25772935; PMID:27098529). Additionally, this variant has been report in at least 4 meioses across 8 families meeting PP1_Moderate. Functional studies performed in mammalian cells demonstrated this variant creates a new signal peptidase cleavage site two amino acids downstream of the normal site, leading to a truncated mature protein missing two amino acids at the N-terminus (PMID:1977621; PMID:27098529). The truncated protein has an increased propensity to form intracellular polymers, which hinders antithrombin secretion (PMID:27098529; PMID:28229161). Transient environmental factors or other predisposing stress events may exacerbate this polymerization and intracellular retention, contributing to the transient deficiency observed in affected individuals (PMID:27098529). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4_Very Strong, PP1_moderate, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA325653/MONDO:0013144/084

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (14 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:5 B:2
• Conservation: PhyloP100: 1.82
• Publications: 24 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 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.89T>A	p.Val30Glu	missense	Exon 2 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.89T>A	p.Val30Glu	missense	Exon 2 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.170T>A	p.Val57Glu	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.89T>A	p.Val30Glu	missense	Exon 2 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.89T>A	p.Val30Glu	missense	Exon 2 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.89T>A	p.Val30Glu	missense	Exon 2 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00179 AC: 449 AN: 251250 AF XY: 0.00177

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00272 AC: 3983 AN: 1461866 Hom.: 14 Cov.: 31 AF XY: 0.00260 AC XY: 1894 AN XY: 727236

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00251 AC: 134 AN: 53404

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

European-Non Finnish (NFE) AF: 0.00328 AC: 3651 AN: 1112004

Other (OTH) AF: 0.00247 AC: 149 AN: 60396

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74490

African (AFR) AF: 0.000553 AC: 23 AN: 41566

American (AMR) AF: 0.000914 AC: 14 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00259 AC: 176 AN: 68036

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00239 Hom.: 0

Bravo AF: 0.00155

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00169 AC: 205

EpiCase AF: 0.00229

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	2	2	Hereditary antithrombin deficiency (7)
2	1	-	not provided (3)
-	1	-	Deep venous thrombosis (1)
-	1	-	Thromboembolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.029	D
Polyphen		0.68	P
Vest4		0.60
MVP		0.61
MPC		0.83
ClinPred		0.0079	T
GERP RS		1.3
Varity_R		0.17
gMVP		0.61
Mutation Taster		=94/6	disease causing (ClinVar)

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: rs2227624; hg19: chr1-173884010;