rs2306581

Positions:

• chr17-42348247-C-A
• chr17-42348247-C-G
• chr17-42348247-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_139276.3(STAT3):​c.128+142G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,260,154 control chromosomes in the GnomAD database, including 101,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (20809 hom., cov: 32)
  • Exomes 𝑓: 0.37 (80486 hom.)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.138

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-42348247-C-A is Benign according to our data. Variant chr17-42348247-C-A is described in ClinVar as [Benign]. Clinvar id is 677148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT3	NM_139276.3	c.128+142G>T		intron_variant		ENST00000264657.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT3	ENST00000264657.10	c.128+142G>T		intron_variant		1	NM_139276.3	A1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72775 AN: 151942 Hom.: 20746 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.431

GnomAD4 exome AF: 0.371 AC: 410821 AN: 1108094 Hom.: 80486 AF XY: 0.372 AC XY: 209476 AN XY: 562764

Gnomad4 AFR exome AF: 0.828

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.370

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.381

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.392

GnomAD4 genome AF: 0.479 AC: 72895 AN: 152060 Hom.: 20809 Cov.: 32 AF XY: 0.478 AC XY: 35541 AN XY: 74324

Gnomad4 AFR AF: 0.808

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.438

Alfa AF: 0.430 Hom.: 2520

Bravo AF: 0.487

Asia WGS AF: 0.543 AC: 1884 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.36

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: rs2306581; hg19: chr17-40500265; COSMIC: COSV52894235;