chr17-42329643-G-C

Position:

• chr17-42329643-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_139276.3(STAT3):​c.1144C>G​(p.Arg382Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R382Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.76

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-42329642-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT3. . Gene score misZ: 4.9943 (greater than the threshold 3.09). Trascript score misZ: 7.3744 (greater than threshold 3.09). The gene has 82 curated pathogenic missense variants (we use a threshold of 10). The gene has 34 curated benign missense variants. GenCC has associacion of the gene with hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3-related early-onset multisystem autoimmune disease, permanent neonatal diabetes mellitus.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3	c.1144C>G	p.Arg382Gly	missense_variant	13/24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.1144C>G	p.Arg382Gly	missense_variant	13/24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.6	M;M;.;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D;.;D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.92
MutPred		0.95		Loss of MoRF binding (P = 0.0165);Loss of MoRF binding (P = 0.0165);.;Loss of MoRF binding (P = 0.0165);Loss of MoRF binding (P = 0.0165);
MVP		0.99
MPC		2.8
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr17-40481661;