17-42313598-T-C

Position:

• chr17-42313598-T-C

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.*2147A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 230,022 control chromosomes in the GnomAD database, including 8,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (6006 hom., cov: 30)
  • Exomes 𝑓: 0.23 (2313 hom.)
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• 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=-0.81).
• BP6: Variant 17-42313598-T-C is Benign according to our data. Variant chr17-42313598-T-C is described in ClinVar as [Benign]. Clinvar id is 323209.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT3	NM_139276.3	c.*2147A>G		3_prime_UTR_variant	24/24	ENST00000264657.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT3	ENST00000264657.10	c.*2147A>G		3_prime_UTR_variant	24/24	1	NM_139276.3	A1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39382 AN: 151564 Hom.: 5994 Cov.: 30

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.233 AC: 18223 AN: 78340 Hom.: 2313 Cov.: 0 AF XY: 0.235 AC XY: 8501 AN XY: 36170

Gnomad4 AFR exome AF: 0.410

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.260 AC: 39432 AN: 151682 Hom.: 6006 Cov.: 30 AF XY: 0.261 AC XY: 19313 AN XY: 74106

Gnomad4 AFR AF: 0.411

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.268

Alfa AF: 0.132 Hom.: 290

Bravo AF: 0.263

Asia WGS AF: 0.394 AC: 1365 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgE recurrent infection syndrome 1, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1053023; hg19: chr17-40465616;