rs121909550
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS3_SupportingPP1_StrongPP3PP4PS4PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000488.4(SERPINC1):c.1277C>T variant predicts a missense change from Serine to Leucine at position 426. Several probands and related individuals are reported in the literature with antithrombin deficiency and the Ser426Leu variant, meeting criteria for PS4 and PP4 (multiple publications). The variant was seen across a total of 8 meioses amongst 3 families meeting PP1_Strong (PMID:30721820, 3512602, 3563966). The variant was shown to impair complex formation with thrombin when the variant was expressed in rabbit reticulocytes (PMID:2207328). The variant is absent in gnomAD (v2.1.1 and v3.1.1) meeting PM2_Supporting. It has a REVEL score of 0.88, which meets the PP3 set threshold (>0.6). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel: PS4, PP1_Strong, PP3, PP4, PS3_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210754/MONDO:0013144/084
Frequency
Consequence
NM_000488.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.1277C>T | p.Ser426Leu | missense_variant | 7/7 | ENST00000367698.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINC1 | ENST00000367698.4 | c.1277C>T | p.Ser426Leu | missense_variant | 7/7 | 1 | NM_000488.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727236
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
ClinVar
Submissions by phenotype
Hereditary antithrombin deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects SERPINC1 protein function (PMID: 3141397). This variant has been observed in individual(s) with clinical features of antithrombin III deficiency (PMID: 3512602, 2602168, 3563966, 18954896, 20088933, 25298121). It has also been observed to segregate with disease in related individuals. This variant is also known as Milano 2, Denver, and S394L in the literature. ClinVar contains an entry for this variant (Variation ID: 18010). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 426 of the SERPINC1 protein (p.Ser426Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 06, 1992 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at