NM_139276.3:c.*1266G>C

Variant names:

• chr17-42314479-C-G
• rs886052938
• NM_139276.3:c.*1266G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_139276.3(STAT3):​c.*1266G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.00042 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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.*1266G>C		3_prime_UTR	Exon 24 of 24	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.*1266G>C		3_prime_UTR	Exon 24 of 24	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.*1266G>C		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.*1266G>C		3_prime_UTR	Exon 24 of 24	ENSP00000264657.4	P40763-1
	STAT3	ENST00000677421.1		c.*1266G>C		3_prime_UTR	Exon 23 of 23	ENSP00000503599.1	A0A7I2V3V0
	STAT3	ENST00000922766.1		c.*1266G>C		3_prime_UTR	Exon 24 of 24	ENSP00000592825.1

Frequencies

GnomAD3 genomes AF: 0.000425 AC: 38 AN: 89410 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.000416

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000384

Gnomad FIN AF: 0.00140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000371

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000879 AC: 5 AN: 5686 Hom.: 0 Cov.: 0 AF XY: 0.000739 AC XY: 2 AN XY: 2706

⚠️ 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: 302

American (AMR) AF: 0.00 AC: 0 AN: 66

Ashkenazi Jewish (ASJ) AF: 0.00266 AC: 1 AN: 376

East Asian (EAS) AF: 0.000703 AC: 1 AN: 1422

South Asian (SAS) AF: 0.00 AC: 0 AN: 52

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.000779 AC: 2 AN: 2568

Other (OTH) AF: 0.00229 AC: 1 AN: 436

⚠️ 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: 0.000425 AC: 38 AN: 89436 Hom.: 0 Cov.: 23 AF XY: 0.000360 AC XY: 15 AN XY: 41674

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

African (AFR) AF: 0.000303 AC: 7 AN: 23114

American (AMR) AF: 0.00101 AC: 7 AN: 6902

Ashkenazi Jewish (ASJ) AF: 0.000416 AC: 1 AN: 2402

East Asian (EAS) AF: 0.00 AC: 0 AN: 3102

South Asian (SAS) AF: 0.000384 AC: 1 AN: 2604

European-Finnish (FIN) AF: 0.00140 AC: 5 AN: 3560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000371 AC: 17 AN: 45766

Other (OTH) AF: 0.00 AC: 0 AN: 1156

⚠️ 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: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.82
DANN	Benign	0.31
PhyloP100		-1.3
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: rs886052938; hg19: chr17-40466497;