17-42324844-A-T

Position:

• chr17-42324844-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_139276.3(STAT3):​c.1467T>A​(p.Asn489Lys) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT3 NM_139276.3 missense, splice_region
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 0.916

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 (HGNC:):

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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3	c.1467T>A	p.Asn489Lys	missense_variant, splice_region_variant	17/24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.1467T>A	p.Asn489Lys	missense_variant, splice_region_variant	17/24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Adenoid cystic carcinoma Other:1

-, no assertion criteria provided

research

Genome Sciences Centre, British Columbia Cancer Agency

Nov 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;D;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.2	M;M;.;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.0	D;.;D;.;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.85
MutPred		0.81		Gain of methylation at N489 (P = 0.0053);Gain of methylation at N489 (P = 0.0053);.;Gain of methylation at N489 (P = 0.0053);Gain of methylation at N489 (P = 0.0053);
MVP		0.94
MPC		2.6
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.86
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1555564365; hg19: chr17-40476862;