rs143521873
Variant summary
Our verdict is Uncertain significance. Variant got -3 ACMG points: 1P and 4B. BS1PP3
This summary comes from the ClinGen Evidence Repository: The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002. One proband in PMID:28300866 and three probands from internal data with AT deficiency are noted to carry the variant ; however PS4 is not applied since BS1 is met. The variant has a REVEL score of 0.873, which exceeds the cutoff (>0.6) set by the VCEP. Thrombosis VCEP considers this variant as a variant of uncertain significance due to the presence of at least 4 cases with AT deficiency and a high REVEL score. While the population frequency is high, the absence of homozygotes in the population may argue against the variant being benign. The experimental evidence is unreliable with varying activity levels on different assays. A conservative approach would be to classify this variant as uncertain. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1251403/MONDO:0013144/084
Frequency
Consequence
NM_000488.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.529C>T | p.Arg177Cys | missense_variant | 3/7 | ENST00000367698.4 | NP_000479.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SERPINC1 | ENST00000367698.4 | c.529C>T | p.Arg177Cys | missense_variant | 3/7 | 1 | NM_000488.4 | ENSP00000356671.3 | ||
SERPINC1 | ENST00000487183.1 | n.234C>T | non_coding_transcript_exon_variant | 2/4 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000539 AC: 82AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251482Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135916
GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727240
GnomAD4 genome AF: 0.000539 AC: 82AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40AN XY: 74352
ClinVar
Submissions by phenotype
Hereditary antithrombin deficiency Uncertain:1Benign:1
Uncertain significance, reviewed by expert panel | curation | Clingen Thrombosis Variant Curation Expert Panel, ClinGen | Sep 21, 2023 | The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002. One proband in PMID: 28300866 and three probands from internal data with AT deficiency are noted to carry the variant ; however PS4 is not applied since BS1 is met. The variant has a REVEL score of 0.873, which exceeds the cutoff (>0.6) set by the VCEP. Thrombosis VCEP considers this variant as a variant of uncertain significance due to the presence of at least 4 cases with AT deficiency and a high REVEL score. While the population frequency is high, the absence of homozygotes in the population may argue against the variant being benign. The experimental evidence is unreliable with varying activity levels on different assays. A conservative approach would be to classify this variant as uncertain. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, PP3. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 02, 2023 | PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at