chr2-73830968-C-G
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_213622.4(STAMBP):c.112C>G(p.Arg38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
STAMBP
NM_213622.4 missense
NM_213622.4 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 2.94
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a region_of_interest Interaction with CHMP3 (size 126) in uniprot entity STABP_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_213622.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-73830968-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.907
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| STAMBP | NM_213622.4 | c.112C>G | p.Arg38Gly | missense_variant | 2/10 | ENST00000394070.7 | NP_998787.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 13, 2022 | This variant disrupts the p.Arg38 amino acid residue in STAMBP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23542699). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1333643). This variant has not been reported in the literature in individuals affected with STAMBP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 38 of the STAMBP protein (p.Arg38Gly). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Microcephaly-capillary malformation syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 07, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Jan 03, 2022 | A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000050793, PM5_M). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.863, PP3_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;D;.;D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;.;D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;M;.;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
T;T;D;T;T;D;T;D
Sift4G
Uncertain
T;T;D;D;T;D;T;D
Polyphen
D;D;.;.;D;.;D;.
Vest4
MutPred
Gain of glycosylation at S39 (P = 0.0225);Gain of glycosylation at S39 (P = 0.0225);Gain of glycosylation at S39 (P = 0.0225);Gain of glycosylation at S39 (P = 0.0225);Gain of glycosylation at S39 (P = 0.0225);Gain of glycosylation at S39 (P = 0.0225);Gain of glycosylation at S39 (P = 0.0225);Gain of glycosylation at S39 (P = 0.0225);
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.