rs397509388
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_213622.4(STAMBP):c.532C>T(p.Arg178Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000105 in 1,614,124 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
STAMBP
NM_213622.4 stop_gained
NM_213622.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.49
Genes affected
STAMBP (HGNC:16950): (STAM binding protein) Cytokine-mediated signal transduction in the JAK-STAT cascade requires the involvement of adaptor molecules. One such signal-transducing adaptor molecule contains an SH3 domain that is required for induction of MYC and cell growth. The protein encoded by this gene binds to the SH3 domain of the signal-transducing adaptor molecule, and plays a critical role in cytokine-mediated signaling for MYC induction and cell cycle progression. Multiple alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-73847543-C-T is Pathogenic according to our data. Variant chr2-73847543-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| STAMBP | NM_213622.4 | c.532C>T | p.Arg178Ter | stop_gained | 5/10 | ENST00000394070.7 | |
| LOC112268419 | XR_007087106.1 | n.358-8641G>A | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| STAMBP | ENST00000394070.7 | c.532C>T | p.Arg178Ter | stop_gained | 5/10 | 1 | NM_213622.4 | P4 | |
| ENST00000650890.1 | n.346-8641G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249812Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135132
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727214
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2023 | ClinVar contains an entry for this variant (Variation ID: 50792). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with microcephaly-capillary malformation syndrome (PMID: 23542699). This variant is present in population databases (rs397509388, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg178*) in the STAMBP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STAMBP are known to be pathogenic (PMID: 23542699). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2023 | Reported in trans with a second STAMBP variant in siblings with microcephaly-capillary malformation syndrome in published literature (McDonell et al., 2013).; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23542699) - |
Microcephaly-capillary malformation syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at