rs587777650

Variant names:

• chr17-42322409-C-A
• rs587777650
• NM_139276.3:c.1974G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-42322409-C-A
• chr17-42322409-C-G
• chr17-42322409-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_139276.3(STAT3):​c.1974G>T​(p.Lys658Asn) variant causes a missense change involving the alteration of a non-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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K658R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.750
• Publications: 20 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: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_139276.3 (STAT3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 144032
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_139276.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-42322410-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 973671.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848
• PP5: Variant 17-42322409-C-A is Pathogenic according to our data. Variant chr17-42322409-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977089.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.1974G>T	p.Lys658Asn	missense_variant	Exon 21 of 24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.1974G>T	p.Lys658Asn	missense_variant	Exon 21 of 24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 04, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This STAT3 variant is absent from a large population dataset and has an entry in ClinVar. It has been reported in two unrelated patients with autosomal dominant infantile-onset multisystem autoimmune disease-1. Independent functional studies have shown that the p.Lys658Asn substitution confers hypersensitivity to interleukins resulting in persistent activation of STAT3 signaling in vitro. This variant is not predicted to affect normal exon 21 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1974G>T to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;D;D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.5	M;M;.;M;M
PhyloP100		0.75
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.7	D;.;D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.034	D;D;D;D;D
Polyphen		0.99	D;.;.;D;D
Vest4		0.89
MutPred		0.53		Loss of ubiquitination at K658 (P = 0.0116);Loss of ubiquitination at K658 (P = 0.0116);.;Loss of ubiquitination at K658 (P = 0.0116);Loss of ubiquitination at K658 (P = 0.0116);
MVP		0.91
MPC		2.6
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.92
gMVP		0.95

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: rs587777650; hg19: chr17-40474427; COSMIC: COSV52886038;