chr1-173903986-G-T

Position:

• chr1-173903986-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000488.4(SERPINC1):​c.1298C>A​(p.Thr433Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.49

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 6 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.2866123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINC1	NM_000488.4	c.1298C>A	p.Thr433Asn	missense_variant	7/7	ENST00000367698.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1298C>A	p.Thr433Asn	missense_variant	7/7	1	NM_000488.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

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: 0.0000306

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SERPINC1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The SERPINC1 c.1298C>A variant is predicted to result in the amino acid substitution p.Thr433Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	.;L
MutationTaster	Benign	0.93	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.13
Sift	Benign	0.49	.;T
Sift4G	Benign	0.34	T;T
Polyphen		0.14	.;B
Vest4		0.27
MutPred		0.34		.;Loss of phosphorylation at T433 (P = 0.0518);
MVP		0.65
MPC		0.45
ClinPred		0.23	T
GERP RS		3.9
Varity_R		0.34
gMVP		0.82

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: chr1-173873124;