rs1026916

Variant names:

• chr17-42377817-A-G
• rs1026916
• NM_139276.3:c.-24+10462T>C

Variant summary

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

The NM_139276.3(STAT3):​c.-24+10462T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 151,806 control chromosomes in the GnomAD database, including 26,314 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 0.57 (26314 hom., cov: 30)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.172
• Publications: 57 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.-24+10462T>C		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.-24+10462T>C		intron_variant	Intron 1 of 23	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86925 AN: 151688 Hom.: 26314 Cov.: 30

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.600

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

GnomAD4 genome AF: 0.573 AC: 86942 AN: 151806 Hom.: 26314 Cov.: 30 AF XY: 0.573 AC XY: 42521 AN XY: 74174

African (AFR) AF: 0.371 AC: 15359 AN: 41366

American (AMR) AF: 0.721 AC: 10990 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2154 AN: 3466

East Asian (EAS) AF: 0.582 AC: 3002 AN: 5154

South Asian (SAS) AF: 0.544 AC: 2618 AN: 4814

European-Finnish (FIN) AF: 0.615 AC: 6473 AN: 10522

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.653 AC: 44348 AN: 67940

Other (OTH) AF: 0.593 AC: 1247 AN: 2102

Alfa AF: 0.619 Hom.: 81439

Bravo AF: 0.571

Asia WGS AF: 0.473 AC: 1650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.48
DANN	Benign	0.66
PhyloP100		0.17
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: rs1026916; hg19: chr17-40529835;