chr17-42313401-AG-A

Variant names:

• chr17-42313401-AG-A
• rs886052929
• NM_139276.3:c.*2343delC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_139276.3(STAT3):​c.*2343delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.290
• Publications: 0 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, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• STAT3-related early-onset multisystem autoimmune disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139276.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	NM_139276.3	MANE Select	c.*2343delC		3_prime_UTR	Exon 24 of 24	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.*2343delC		3_prime_UTR	Exon 24 of 24	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.*2343delC		3_prime_UTR	Exon 24 of 24	NP_001356442.1	P40763-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	ENST00000264657.10	TSL:1 MANE Select	c.*2343delC		3_prime_UTR	Exon 24 of 24	ENSP00000264657.4	P40763-1
	STAT3	ENST00000922766.1		c.*2343delC		3_prime_UTR	Exon 24 of 24	ENSP00000592825.1
	STAT3	ENST00000922763.1		c.*2343delC		3_prime_UTR	Exon 24 of 24	ENSP00000592822.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 38 AN: 144326 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000100

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.000346

Gnomad ASJ AF: 0.000303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000427

Gnomad FIN AF: 0.000216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000341

Gnomad OTH AF: 0.000508

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000218 AC: 1 AN: 45888 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 21264

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 1872

American (AMR) AF: 0.00 AC: 0 AN: 1244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2896

East Asian (EAS) AF: 0.000132 AC: 1 AN: 7562

South Asian (SAS) AF: 0.00 AC: 0 AN: 384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 27428

Other (OTH) AF: 0.00 AC: 0 AN: 3778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000263 AC: 38 AN: 144404 Hom.: 0 Cov.: 27 AF XY: 0.000241 AC XY: 17 AN XY: 70418

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000100 AC: 4 AN: 40010

American (AMR) AF: 0.000346 AC: 5 AN: 14468

Ashkenazi Jewish (ASJ) AF: 0.000303 AC: 1 AN: 3296

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.000429 AC: 2 AN: 4666

European-Finnish (FIN) AF: 0.000216 AC: 2 AN: 9278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000341 AC: 22 AN: 64426

Other (OTH) AF: 0.000503 AC: 1 AN: 1990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000558 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Hyper-IgE syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29

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: rs886052929; hg19: chr17-40465419; COSMIC: COSV52886508; COSMIC: COSV52886508;