17-42313404-C-CA

Variant names:

• chr17-42313404-C-CA
• rs886052930
• NM_139276.3:c.*2340dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_139276.3(STAT3):​c.*2340dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 144,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0770
• 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, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• STAT3-related early-onset multisystem autoimmune disease

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (32/118830) while in subpopulation SAS AF = 0.002 (7/3506). AF 95% confidence interval is 0.000936. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 32 AD gene.

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.*2340dupT		3_prime_UTR	Exon 24 of 24	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.*2340dupT		3_prime_UTR	Exon 24 of 24	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.*2340dupT		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.*2340dupT		3_prime_UTR	Exon 24 of 24	ENSP00000264657.4	P40763-1
	STAT3	ENST00000922766.1		c.*2340dupT		3_prime_UTR	Exon 24 of 24	ENSP00000592825.1
	STAT3	ENST00000922763.1		c.*2340dupT		3_prime_UTR	Exon 24 of 24	ENSP00000592822.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 32 AN: 118804 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000938

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00199

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000362

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000196 AC: 5 AN: 25492 Hom.: 0 Cov.: 0 AF XY: 0.000169 AC XY: 2 AN XY: 11814

African (AFR) AF: 0.00 AC: 0 AN: 884

American (AMR) AF: 0.00350 AC: 2 AN: 572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1654

East Asian (EAS) AF: 0.00 AC: 0 AN: 4758

South Asian (SAS) AF: 0.00 AC: 0 AN: 240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 292

Middle Eastern (MID) AF: 0.00602 AC: 1 AN: 166

European-Non Finnish (NFE) AF: 0.0000674 AC: 1 AN: 14844

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

GnomAD4 genome AF: 0.000269 AC: 32 AN: 118830 Hom.: 0 Cov.: 31 AF XY: 0.000368 AC XY: 21 AN XY: 57096

African (AFR) AF: 0.0000937 AC: 3 AN: 32024

American (AMR) AF: 0.000163 AC: 2 AN: 12304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2912

East Asian (EAS) AF: 0.00 AC: 0 AN: 3920

South Asian (SAS) AF: 0.00200 AC: 7 AN: 3506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.000363 AC: 20 AN: 55168

Other (OTH) AF: 0.00 AC: 0 AN: 1660

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyper-IgE syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.077
Mutation Taster		=100/0	polymorphism

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: rs886052930; hg19: chr17-40465422;