rs786204063
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate
The NM_000488.4(SERPINC1):c.462_464del(p.Phe155del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SERPINC1
NM_000488.4 inframe_deletion
NM_000488.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.60
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.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000488.4
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000488.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 1-173911958-AAAG-A is Pathogenic according to our data. Variant chr1-173911958-AAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 188092.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.462_464del | p.Phe155del | inframe_deletion | 3/7 | ENST00000367698.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINC1 | ENST00000367698.4 | c.462_464del | p.Phe155del | inframe_deletion | 3/7 | 1 | NM_000488.4 | P1 | |
SERPINC1 | ENST00000487183.1 | n.167_169del | non_coding_transcript_exon_variant | 2/4 | 2 | ||||
SERPINC1 | ENST00000494024.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary antithrombin deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 06, 2015 | In summary, this small deletion is absent from the general population and reported in individuals affected with type I antithrombin deficiency. For these reasons, it has been classified as Pathogenic. This variant has been reported in the literature in individuals affected with type I antithrombin deficiency (PMID: 8217824, 9701453,8401542), and is not present in population databases. In the affected individuals reported to carry this in-frame deletion, the activity of ATIII was reduced 47 to 62% of normal  (PMID: 8217824, 9701453,8401542). In the literature, this variant is also known as c.5356_5364delCTT. This sequence change deletes 3 nucleotides in exon 3 of the SERPINC1 mRNA (c.462_464delCTT ). This leads to the  deletion of one phenylalanine residue in the SERPINC1 protein (p.Phe155del) but otherwise preserves the integrity of the reading frame. - |
Computational scores
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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