1-173914743-G-C

Variant names:

• chr1-173914743-G-C
• NM_000488.4:c.218C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000488.4(SERPINC1):​c.218C>G​(p.Pro73Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P73L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.42

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 6 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 chr1-173914743-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18011.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.218C>G	p.Pro73Arg	missense_variant	Exon 2 of 7	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.218C>G	p.Pro73Arg	missense_variant	Exon 2 of 7	1	NM_000488.4	ENSP00000356671.3
SERPINC1	ENST00000494024.1	n.444C>G		non_coding_transcript_exon_variant	Exon 3 of 4	3
SERPINC1	ENST00000487183.1	n.-78C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0050	.;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	.;D
Vest4		0.82
MutPred		0.23		Gain of MoRF binding (P = 0.0113);Gain of MoRF binding (P = 0.0113);
MVP		0.92
MPC		1.2
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.41
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-173883881;