rs113994135

Positions:

• chr17-42329643-G-A
• chr17-42329643-G-C
• chr17-42329643-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_139276.3(STAT3):​c.1144C>T​(p.Arg382Trp) 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 (★★). 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: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• 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 Pathogenic. Variant got 17 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, 0.984
• PP5: Variant 17-42329643-G-A is Pathogenic according to our data. Variant chr17-42329643-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42329643-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3	c.1144C>T	p.Arg382Trp	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>T	p.Arg382Trp	missense_variant	13/24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgE recurrent infection syndrome 1, autosomal dominant Pathogenic:6 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 08, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	May 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Dec 20, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 18, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000018304) and a different missense change at the same codon(p.Arg382Gln; ClinVar ID: VCV000018305) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21606497, 23040277, 22581330, 22500887, 24452316, 17881745, 23830147, 32248557, 27315770, 21324546, 17942886, 21288777, 17676033, 26384563, 26293184, 20093388, 27799162, 4161105, 29620631, 30697212, 30410549, 30732127, 31346092, 31596517, 31681265, 32047500, 32135276, 32912316, 32768442, 33343952, 32915432, 33225392, 32944025, 32888943, 33014947, 34134972, 33717144, 18602572) -

STAT3-related early-onset multisystem autoimmune disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine

Jan 03, 2023

- -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4014795:STAT3-related early-onset multisystem autoimmune disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PS3+PM6+PS4_Moderate+PM5+PM2_Supporting+PP4 -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 382 of the STAT3 protein (p.Arg382Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper IgE syndrome (HIES) (PMID: 17676033, 17881745, 17942886, 21324546, 24452316). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STAT3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 17676033, 22581330). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.3	M;M;.;M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.6	D;.;D;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.96
MutPred		0.97		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.97
MPC		2.5
ClinPred		1.0	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

LitVar

Other links and lift over

dbSNP: rs113994135; hg19: chr17-40481661; COSMIC: COSV52890703; COSMIC: COSV52890703;