17-42322395-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_139276.3(STAT3):​c.1988C>A​(p.Thr663Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

STAT3
NM_139276.3 missense

Scores

3
11
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.67
Variant links:
Genes affected
STAT3 (HGNC:11364): (signal transducer and activator of transcription 3) 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. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain SH2 (size 90) in uniprot entity STAT3_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_139276.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the STAT3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 82 curated pathogenic missense variants (we use a threshold of 10). The gene has 34 curated benign missense variants. Gene score misZ: 4.9943 (above the threshold of 3.09). Trascript score misZ: 7.3744 (above the threshold of 3.09). GenCC associations: The gene is linked to hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3-related early-onset multisystem autoimmune disease, permanent neonatal diabetes mellitus.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STAT3NM_139276.3 linkc.1988C>A p.Thr663Asn missense_variant Exon 21 of 24 ENST00000264657.10 NP_644805.1 P40763-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STAT3ENST00000264657.10 linkc.1988C>A p.Thr663Asn missense_variant Exon 21 of 24 1 NM_139276.3 ENSP00000264657.4 P40763-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.53
D;.;T;D;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
.;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.44
T;T;T;T;T
MetaSVM
Uncertain
0.43
D
MutationAssessor
Benign
-0.90
N;N;.;N;N
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
0.46
N;.;N;.;N
REVEL
Uncertain
0.48
Sift
Uncertain
0.019
D;.;D;.;D
Sift4G
Benign
0.46
T;T;T;T;T
Polyphen
0.99
D;.;.;D;D
Vest4
0.51
MutPred
0.58
Loss of methylation at K658 (P = 0.0999);Loss of methylation at K658 (P = 0.0999);.;Loss of methylation at K658 (P = 0.0999);Loss of methylation at K658 (P = 0.0999);
MVP
0.71
MPC
2.3
ClinPred
0.96
D
GERP RS
4.5
Varity_R
0.36
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40474413; API