rs121909572

Positions:

• chr1-173910849-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000488.4(SERPINC1):​c.667T>C​(p.Ser223Pro) variant causes a missense change involving the alteration of a non-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 (no stars). Synonymous variant affecting the same amino acid position (i.e. S223S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.581

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000488.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 1-173910849-A-G is Pathogenic according to our data. Variant chr1-173910849-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 18043.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.667T>C	p.Ser223Pro	missense_variant	4/7	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.667T>C	p.Ser223Pro	missense_variant	4/7	1	NM_000488.4	ENSP00000356671.3
SERPINC1	ENST00000487183.1	n.330-12T>C		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.80	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.62
Sift	Benign	0.035	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.77
MutPred		0.71		Gain of methylation at K220 (P = 0.0462);
MVP		0.92
MPC		1.2
ClinPred		0.97	D
GERP RS		-0.57
Varity_R		0.92
gMVP		0.89

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: rs121909572; hg19: chr1-173879987;