rs121909555
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP1_ModeratePP3PM5PS4_SupportingPM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1316C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 439 (p.Pro439Leu). This variant has been reported in one proband meeting the phenotypic criteria of an antithrombin activity level of < 0.8 IU/mL and a positive family history. (PS4_Supporting; PMIDs: 6877092, 3191114). 12 segregations are counted in the Utah family where 13 members are identified as AT-deficient. 11 individuals showed electrophoretically abnormal AT; 2 individuals are obligate carriers. PMID:3191114 performed sequence analysis on this family. Based on RFLP analysis in this paper, 12 segregations may be counted. However, criteria for PP1_Strong is not met as segregations across >1 family is required (PP1_Moderate; PMID:2983542, 3191114). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.952, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1315C>A (p.Pro439Thr) (ClinVarID:627228) in the same codon has been classified as pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5).In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PM5, PP3, PM2, PS4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) LINK:https://erepo.genome.network/evrepo/ui/classification/CA210764/MONDO:0013144/084
Frequency
Consequence
NM_000488.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.1316C>T | p.Pro439Leu | missense_variant | 7/7 | ENST00000367698.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINC1 | ENST00000367698.4 | c.1316C>T | p.Pro439Leu | missense_variant | 7/7 | 1 | NM_000488.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary antithrombin deficiency Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | Clingen Thrombosis Variant Curation Expert Panel, ClinGen | Jan 25, 2024 | The c.1316C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 439 (p.Pro439Leu). This variant has been reported in one proband meeting the phenotypic criteria of an antithrombin activity level of < 0.8 IU/mL and a positive family history. (PS4_Supporting; PMIDs: 6877092, 3191114). 12 segregations are counted in the Utah family where 13 members are identified as AT-deficient. 11 individuals showed electrophoretically abnormal AT; 2 individuals are obligate carriers. PMID: 3191114 performed sequence analysis on this family. Based on RFLP analysis in this paper, 12 segregations may be counted. However, criteria for PP1_Strong is not met as segregations across >1 family is required (PP1_Moderate; PMID:2983542, 3191114). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.952, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1315C>A (p.Pro439Thr) (ClinVarID:627228) in the same codon has been classified as pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PM5, PP3, PM2, PS4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 09, 1988 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at