rs1800578
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000361.3(THBD):c.1483C>T(p.Pro495Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,609,724 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000361.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
THBD | NM_000361.3 | c.1483C>T | p.Pro495Ser | missense_variant | 1/1 | ENST00000377103.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
THBD | ENST00000377103.3 | c.1483C>T | p.Pro495Ser | missense_variant | 1/1 | NM_000361.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000670 AC: 102AN: 152252Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000493 AC: 117AN: 237468Hom.: 0 AF XY: 0.000433 AC XY: 56AN XY: 129422
GnomAD4 exome AF: 0.00144 AC: 2101AN: 1457352Hom.: 2 Cov.: 30 AF XY: 0.00137 AC XY: 992AN XY: 724712
GnomAD4 genome ? AF: 0.000669 AC: 102AN: 152372Hom.: 1 Cov.: 33 AF XY: 0.000631 AC XY: 47AN XY: 74512
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | THBD: BP4, BS1, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 19, 2021 | - - |
Atypical hemolytic-uremic syndrome Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Sep 06, 2018 | This patient is heterozygous for a known pathogenic variant, c.1483C>T (p.Pro495Ser), in the THBD gene. This variant (dbSNP: rs1800578) is in the ExAC database (http://exac.broadinstitute.org) with an allele frequency of 0.10% (51/50264 alleles) in the European non-Finnish population. It has also been reported in a patient with recurrent atypical hemolytic-uremic syndrome (aHUS) with the first episode at 3 years of age. Other clinical findings were residual renal dysfunction and low serum C3 levels (Delvaeye et al 2009 N Eng J Med 361:345-57). The authors also performed in vitro functional studies which showed the mutant THBD protein did not protect against complement activation. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 13, 2021 | - - |
Thrombomodulin-related bleeding disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
THBD-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 05, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Atypical hemolytic-uremic syndrome with thrombomodulin anomaly Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jul 23, 2009 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at