rs121909567
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000488.4(SERPINC1):c.391C>T(p.Leu131Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,034 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L131V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000488.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.391C>T | p.Leu131Phe | missense_variant | 2/7 | ENST00000367698.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINC1 | ENST00000367698.4 | c.391C>T | p.Leu131Phe | missense_variant | 2/7 | 1 | NM_000488.4 | P1 | |
SERPINC1 | ENST00000487183.1 | n.96C>T | non_coding_transcript_exon_variant | 1/4 | 2 | ||||
SERPINC1 | ENST00000494024.1 | n.617C>T | non_coding_transcript_exon_variant | 3/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251466Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Hereditary antithrombin deficiency Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 11, 1990 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 08, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 131 of the SERPINC1 protein (p.Leu131Phe). This variant is present in population databases (rs121909567, gnomAD 0.004%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 22498748, 24072242, 24158114, 26748602). It has also been observed to segregate with disease in related individuals. This variant is also known as p.L99F. ClinVar contains an entry for this variant (Variation ID: 18034). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 1555650, 22498748, 29215785). - |
Pathogenic, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 22, 2021 | - - |
Pathogenic, reviewed by expert panel | curation | Clingen Thrombosis Variant Curation Expert Panel, ClinGen | Sep 21, 2023 | The c.391C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 131 (p.Leu131Phe; legacy nomenclature p.Leu99Phe, Antithrombin Budapest 3 (ATBp3)). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003516 (4/113752 alleles) in the non-Finnish European population, which does not meet criteria for PM2_Supporting (MAF =< 2.0 X 10-5 in gnomAD). The computational predictor REVEL gives a score of 0.853, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function (PP3). The variant has been reported to segregate with AT deficiency in at least 11 affected family members from 2 families (PP1_Strong; PMIDs: 32686144, 24072242). This variant has been reported in at least 100 probands with AT deficiency and is a founder variant in the Hugarian population. Further studies of the Hungarian cohort demonstrated that homozygosity was associated with thrombosis at a younger age and led to a high thrombotic risk while the heterozygous carriers also had venous and/or arterial thrombosis, as well as pregnancy complications. This variant was also reported in internal laboratory data (PS4_Very Strong; PMIDs: 26748602, 1555650, 32686144). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_strong, PP3, PS4_Very Strong - |
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Deep venous thrombosis Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at