rs567550044
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_000488.4(SERPINC1):c.995C>T(p.Thr332Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,172 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
SERPINC1
NM_000488.4 missense
NM_000488.4 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 1.41
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
?
In a disulfide_bond (size 183) in uniprot entity ANT3_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000488.4
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.37129492).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.995C>T | p.Thr332Ile | missense_variant | 5/7 | ENST00000367698.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINC1 | ENST00000367698.4 | c.995C>T | p.Thr332Ile | missense_variant | 5/7 | 1 | NM_000488.4 | P1 | |
SERPINC1 | ENST00000487183.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 34
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251376Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135860
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461816Hom.: 0 Cov.: 48 AF XY: 0.00000275 AC XY: 2AN XY: 727218
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152356Hom.: 0 Cov.: 34 AF XY: 0.0000268 AC XY: 2AN XY: 74506
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary antithrombin deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2015 | This variant is present in population databases (rs567550044, ExAC 0.02%) but has not been reported in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This sequence change replaces threonine with isoleucine at codon 332 of the SERPINC1 protein (p.Thr332Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at