rs2227624

Positions:

• chr1-173914872-A-T

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 10P and 4B. PS3 PS4 BS1 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 antithrombin Dublin). 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 III 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). The variant is reported at a popmax FAF of 0.001705 and the highest MAF of 0.002859 (369/129044 alleles with 2 homozygotes) in the European population in gnomAD v2.1.1. BA1 does not necessarily apply as a stand alone evidence because patients will appear normal under most situations. BS1 was applied to account for the large population frequency. 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. BS1, 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5 B:2
• Conservation: PhyloP100: 1.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 6 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.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.89T>A	p.Val30Glu	missense_variant	2/7	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.89T>A	p.Val30Glu	missense_variant	2/7	1	NM_000488.4	ENSP00000356671	P1
SERPINC1	ENST00000494024.1	n.315T>A		non_coding_transcript_exon_variant	3/4	3

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

GnomAD3 exomes AF: 0.00179 AC: 449 AN: 251250 Hom.: 2 AF XY: 0.00177 AC XY: 240 AN XY: 135800

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 SAS 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

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00251

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.00247

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

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.00237

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:2 Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1992	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2021	Reported as AT Dublin in the literature (Daly et al., 1987); Published functional studies demonstrate impaired secretion and negligible inhibitory activity (Daly et al., 1990; Navarro-Fernndez et al., 2016).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1977621, 1483705, 31064749, 31894660, 29450643, 31885188, 28607330, 3472589, 23910795, 25496998, 24121110, 27098529, 31157679, 30721820) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 01, 2022	PP1_strong, PM1, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SERPINC1: PS4, PM1, PP1, BP4 -

Thromboembolism Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Deep venous thrombosis Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	.;D
Sift4G	Uncertain	0.029	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2227624; hg19: chr1-173884010;