17-42322404-A-G

Position:

• chr17-42322404-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_139276.3(STAT3):​c.1979T>C​(p.Met660Thr) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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 15 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 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). GenCC has associacion of 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, 0.869
• PP5: Variant 17-42322404-A-G is Pathogenic according to our data. Variant chr17-42322404-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3	c.1979T>C	p.Met660Thr	missense_variant	21/24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.1979T>C	p.Met660Thr	missense_variant	21/24	1	NM_139276.3	ENSP00000264657	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

STAT3 gain of function;CN031130:Hyper-IgE recurrent infection syndrome 1, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2018

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met660 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 21792878), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change disrupts protein function (PMID: 28315006, 29868029). This variant has been observed in individuals affected with hyper IgE syndrome, including an individual in which the variant occurred de novo (PMID: PMID: 20816194, 28315006). ClinVar contains an entry for this variant (Variation ID: 265261). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 660 of the STAT3 protein (p.Met660Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2016

The M660T variant has been published in association with hyper IgE syndrome (Schimke et al., 2010). The M660T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M660T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position located within the SH2 domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic. -

Hyper-IgE syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 15, 2016

Variant summary: The STAT3 c.1979T>C (p.Met660Thr) variant involves the alteration of a conserved nucleotide located in the Src homology domain 2 of STAT3 and results in a replacement of a medium size and hydrophobic Methionine (M) with a medium size and polar Threonine (T). 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121612 control chromosomes while it was reported in Hyper IgE Syndrome patients indicating pathogenicity. Moreover, in one patient, the variant emerged de novo strongly suggesting a deleterious outcome. Studies assessing the impact the variant may have on the function of the STAT3 protein were not published at the time of classification. Taken together, this variant is classified as probably pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.;D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	.;T;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.2	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.5	D;.;D;.;D
REVEL	Pathogenic	0.87
Sift	Benign	0.030	D;.;D;.;D
Sift4G	Benign	0.081	T;T;T;T;T
Polyphen		0.59	P;.;.;P;P
Vest4		0.94
MutPred		0.48		Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);.;Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);
MVP		0.99
MPC		1.6
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.82
gMVP		0.91

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: rs886039434; hg19: chr17-40474422;