rs1905340

Variant names:

• chr17-42368372-C-A
• rs1905340
• NM_139276.3:c.-23-19833G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139276.3(STAT3):​c.-23-19833G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,100 control chromosomes in the GnomAD database, including 7,294 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7294 hom., cov: 32)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.276
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.-23-19833G>T		intron_variant	Intron 1 of 23	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.-23-19833G>T		intron_variant	Intron 1 of 23	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45961 AN: 151982 Hom.: 7281 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.303 AC: 46012 AN: 152100 Hom.: 7294 Cov.: 32 AF XY: 0.304 AC XY: 22573 AN XY: 74338

African (AFR) AF: 0.370 AC: 15367 AN: 41486

American (AMR) AF: 0.207 AC: 3157 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1159 AN: 3466

East Asian (EAS) AF: 0.398 AC: 2061 AN: 5172

South Asian (SAS) AF: 0.382 AC: 1844 AN: 4828

European-Finnish (FIN) AF: 0.283 AC: 2990 AN: 10568

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18493 AN: 67988

Other (OTH) AF: 0.297 AC: 628 AN: 2114

Alfa AF: 0.287 Hom.: 827

Bravo AF: 0.301

Asia WGS AF: 0.418 AC: 1450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.46
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs1905340; hg19: chr17-40520390;