rs8069115

Positions:

• chr17-42317162-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264657.10(STAT3):​c.2144+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,918 control chromosomes in the GnomAD database, including 596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (311 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (285 hom.)
• Consequence: STAT3 ENST00000264657.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.53

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 17-42317162-G-A is Benign according to our data. Variant chr17-42317162-G-A is described in ClinVar as [Benign]. Clinvar id is 262464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42317162-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3	c.2144+20C>T		intron_variant		ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.2144+20C>T		intron_variant		1	NM_139276.3	ENSP00000264657	A1

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5073 AN: 152088 Hom.: 307 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0221

GnomAD3 exomes AF: 0.00954 AC: 2395 AN: 251128 Hom.: 116 AF XY: 0.00704 AC XY: 955 AN XY: 135734

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00689

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00402 AC: 5879 AN: 1461712 Hom.: 285 Cov.: 31 AF XY: 0.00354 AC XY: 2577 AN XY: 727150

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.00779

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00200

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000455

Gnomad4 OTH exome AF: 0.00946

GnomAD4 genome AF: 0.0336 AC: 5109 AN: 152206 Hom.: 311 Cov.: 31 AF XY: 0.0330 AC XY: 2453 AN XY: 74426

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0219

Alfa AF: 0.0204 Hom.: 42

Bravo AF: 0.0383

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.35
DANN	Benign	0.79
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: rs8069115; hg19: chr17-40469180;