rs869312891

Variant names:

• chr17-42331524-C-A
• rs869312891
• NM_139276.3:c.1057G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_139276.3(STAT3):​c.1057G>T​(p.Val353Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V353V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.13
• Publications: 7 publications found

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]

STAT3 Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 1, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• STAT3-related early-onset multisystem autoimmune disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 17-42331524-C-A is Pathogenic according to our data. Variant chr17-42331524-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224847.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.1057G>T	p.Val353Phe	missense_variant	Exon 11 of 24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.1057G>T	p.Val353Phe	missense_variant	Exon 11 of 24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461430 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111712

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 30, 2014

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

segregates with the phenotype in an affected family -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.4	M;M;.;M;M
PhyloP100		6.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D;.;D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.94
MutPred		0.74		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.99
MPC		2.8
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.91
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869312891; hg19: chr17-40483542;