rs758087836
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000488.4(SERPINC1):c.805G>A(p.Glu269Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
SERPINC1
NM_000488.4 missense
NM_000488.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 3.07
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.954
PP5
?
Variant 1-173909900-C-T is Pathogenic according to our data. Variant chr1-173909900-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410383.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.805G>A | p.Glu269Lys | missense_variant | 5/7 | ENST00000367698.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINC1 | ENST00000367698.4 | c.805G>A | p.Glu269Lys | missense_variant | 5/7 | 1 | NM_000488.4 | P1 | |
SERPINC1 | ENST00000487183.1 | n.456G>A | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250712Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135524
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461830Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 727228
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74386
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 30, 2022 | PP1, PM1, PM2, PS4_supporting - |
Hereditary antithrombin deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 31, 2016 | This sequence change replaces glutamic acid with lysine at codon 269 of the SERPINC1 protein (p.Glu269Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs758087836, ExAC 0.003%). This variant has been reported in a 37 year old male with cerebellar venous infarct, deep vein thrombosis, and pulmonary emboli and recovered following treatment with antithrombin III (AT-III) concentrate. Family studies showed that this variant segregated in three individuals with reduced concentrations of AT-III plus venous thromboembolism (VTE), one individual with reduced AT-III concentrations but no VTE, and an unaffected 17 year old female family member (PMID: 1430264). This variant is also known as 237 Glu to Lys or Truro variant in the literature. Experimental studies have shown that this missense change alters heparin pentasaccharide affinity and binding kinetics in vitro suggesting that this amino acid residue is important for protein function (PMID: 10966821, 16973611). In summary, this missense change has been reported to alter binding to heparin in vitro and segregates in a family with history of venous thromboembolism. However, this variant is also present in population databases and without additional functional and/or genetic data, this change has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of ubiquitination at K268 (P = 0.0074);
MVP
MPC
ClinPred
T
GERP RS
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