rs7211777

Variant names:

• chr17-42382057-G-A
• rs7211777
• NM_139276.3:c.-24+6222C>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.-24+6222C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,996 control chromosomes in the GnomAD database, including 24,074 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 0.52 (24074 hom., cov: 31)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01
• Publications: 31 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=-0.72).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.-24+6222C>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.-24+6222C>T		intron_variant	Intron 1 of 23	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79771 AN: 151878 Hom.: 24075 Cov.: 31

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.572

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

GnomAD4 genome AF: 0.525 AC: 79768 AN: 151996 Hom.: 24074 Cov.: 31 AF XY: 0.526 AC XY: 39083 AN XY: 74294

African (AFR) AF: 0.206 AC: 8523 AN: 41466

American (AMR) AF: 0.703 AC: 10721 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2155 AN: 3470

East Asian (EAS) AF: 0.583 AC: 3005 AN: 5152

South Asian (SAS) AF: 0.538 AC: 2592 AN: 4820

European-Finnish (FIN) AF: 0.616 AC: 6519 AN: 10582

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.652 AC: 44315 AN: 67944

Other (OTH) AF: 0.565 AC: 1194 AN: 2112

Alfa AF: 0.594 Hom.: 12993

Bravo AF: 0.518

Asia WGS AF: 0.457 AC: 1593 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.66
PhyloP100		3.0
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: rs7211777; hg19: chr17-40534075;