17-42329431-A-C

Position:

• chr17-42329431-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_139276.3(STAT3):​c.1260T>G​(p.Asn420Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.283

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 Uncertain_significance. Variant got 5 ACMG points.

• 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.
• PP5: Variant 17-42329431-A-C is Pathogenic according to our data. Variant chr17-42329431-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 224849.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3	c.1260T>G	p.Asn420Lys	missense_variant	14/24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.1260T>G	p.Asn420Lys	missense_variant	14/24	1	NM_139276.3	ENSP00000264657	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Oct 30, 2014

segregates with the phenotype in an affected family -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;D;D;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.90	L;L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N;.;N;.;N
REVEL	Pathogenic	0.80
Sift	Benign	0.072	T;.;T;.;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.93	P;.;.;P;P
Vest4		0.74
MutPred		0.53		Gain of ubiquitination at N420 (P = 0.0155);Gain of ubiquitination at N420 (P = 0.0155);.;Gain of ubiquitination at N420 (P = 0.0155);Gain of ubiquitination at N420 (P = 0.0155);
MVP		0.88
MPC		1.5
ClinPred		0.95	D
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs869312893; hg19: chr17-40481449;