rs121909546

chr1-173903978-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000488.4(SERPINC1):c.1306G>A(p.Ala436Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.22

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000488.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 1-173903978-C-T is Pathogenic according to our data. Variant chr1-173903978-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18003.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINC1	NM_000488.4	c.1306G>A	p.Ala436Thr	missense_variant	7/7	ENST00000367698.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1306G>A	p.Ala436Thr	missense_variant	7/7	1	NM_000488.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 16, 1988	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 29, 2018	For these reasons, this variant has been classified as Pathogenic. Experimental studies using both patient cells and transfected cell lines have shown that cells carrying this missense variant demonstrate reduced antithrombin activity and antigen levels (PMID: 1469094, 16620552). This variant has been reported to segregate with antithrombin deficiency in several families (PMID: 1469094, 16620552). ClinVar contains an entry for this variant (Variation ID: 18003). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 436 of the SERPINC1 protein (p.Ala436Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.52	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.60	T
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.77		.;Gain of phosphorylation at A436 (P = 0.0739);
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909546; hg19: chr1-173873116;