rs387906767
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5
The NM_007315.4(STAT1):c.493G>C(p.Asp165His) variant causes a missense change. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D165G) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
STAT1
NM_007315.4 missense
NM_007315.4 missense
Scores
7
9
1
Clinical Significance
Conservation
PhyloP100: 6.00
Genes affected
STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_007315.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr2-190999673-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30089.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
?
Missense variant where missense usually causes diseases, STAT1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.752
PP5
?
Variant 2-190999674-C-G is Pathogenic according to our data. Variant chr2-190999674-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 30092.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-190999674-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STAT1 | NM_007315.4 | c.493G>C | p.Asp165His | missense_variant | 7/25 | ENST00000361099.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STAT1 | ENST00000361099.8 | c.493G>C | p.Asp165His | missense_variant | 7/25 | 1 | NM_007315.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;.
Polyphen
P;.;P;P;.;.
Vest4
MutPred
Loss of ubiquitination at K161 (P = 0.0777);Loss of ubiquitination at K161 (P = 0.0777);Loss of ubiquitination at K161 (P = 0.0777);Loss of ubiquitination at K161 (P = 0.0777);.;Loss of ubiquitination at K161 (P = 0.0777);
MVP
MPC
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