rs121909552

chr1-173914725-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000488.4(SERPINC1):c.236G>A(p.Arg79His) variant causes a missense change. The variant allele was found at a frequency of 0.000225 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R79S) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:2 B:1
• Conservation: PhyloP100: 5.83

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 13 ACMG points.

• PM1: In a disulfide_bond (size 74) in uniprot entity ANT3_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_000488.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-173914726-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-173914725-C-T is Pathogenic according to our data. Variant chr1-173914725-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18014.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3754798).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINC1	NM_000488.4	c.236G>A	p.Arg79His	missense_variant	2/7	ENST00000367698.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINC1	ENST00000367698.4	c.236G>A	p.Arg79His	missense_variant	2/7	1	NM_000488.4	P1
SERPINC1	ENST00000494024.1	n.462G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000954 AC: 24 AN: 251464 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135904

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 337 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.000246 AC XY: 179 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74498

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000361 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:6 Uncertain:2 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 79 of the SERPINC1 protein (p.Arg79His). This variant is present in population databases (rs121909552, gnomAD 0.02%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 2363123, 2615648, 3567355, 7981186, 21264449, 25837307, 26748602, 28607330, 29153735, 31885188, 35626216). This variant is also known as R47H, Arg47His, AT Padua I, AT Rouen I, or AT III Bligny. ClinVar contains an entry for this variant (Variation ID: 18014). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINC1 protein function with a negative predictive value of 95%. This variant disrupts the p.Arg79 (also known as p.Arg47) amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 6582486, 21325262, 24162787, 28300866). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Sep 21, 2023	The c.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant is an established founder variant known as AT Padua I making it ineligible for the BS1 rule application. It has a REVEL score of 0.702, and meets PP3. At least 23 individuals with AT deficiency meeting the SERPINC1 phenotype criteria (other cases are reported but do not meet criteria) are reported in the literature meeting PS4_Very Strong and PP4. Additionally, 9 meioses have been reported across 16 families meeting PP1_Strong. In summary, this variant reaches a classification of pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Strong, PM1, PP3, PP4. -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 03, 2017	The SERPINC1 c.236G>A (p.Arg79His) missense variant has been identified in a heterozygous state in five patients with antithrombin-III (AT) deficiency (Orlando et al. 2015). Gindele et al. (2016) also reported this variant in 6.7% of patients with type II heparin binding site deficiency (HBS). In the Orlando et al. (2015) study, two patients each also had arterial events and venous thrombotic events, respectively. However, another study indicated that endogenous thrombin potential was not increased in carriers of the p.Arg79His variant, thereby suggesting that this variant is associated with a low risk of venous thromboembolism (Alhenc-Gelas et al. 2010). In addition, using multiple commercially available methods, AT activity was measured in the five patients from the Orlando et al. (2015) study and activity was decreased in some cases, but some of these methods did not show decreased activity. Another variant at this amino acid position, p.Arg79Cys, has also been observed in patients (Orlando et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg79His variant is classified as a variant of unknown significance but suspicious for pathogenicity for antithrombin-III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 16, 2021	PS4_Moderate, PM1, PM2, PM5, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	SERPINC1: PS1, PM1, PP1, PP4, PS3:Supporting, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.086	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.017	D;D
Polyphen		0.98	.;D
Vest4		0.67
MVP		0.94
MPC		0.79
ClinPred		0.19	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.81

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: rs121909552; hg19: chr1-173883863; COSMIC: COSV62930719; COSMIC: COSV62930719;