17-42348247-C-A

Variant names:

• chr17-42348247-C-A
• rs2306581
• NM_139276.3:c.128+142G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139276.3(STAT3):​c.128+142G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,260,154 control chromosomes in the GnomAD database, including 101,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20809 hom., cov: 32)
  • Exomes 𝑓: 0.37 (80486 hom.)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.138
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-42348247-C-A is Benign according to our data. Variant chr17-42348247-C-A is described in ClinVar as Benign. ClinVar VariationId is 677148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

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.128+142G>T		intron	N/A	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.128+142G>T		intron	N/A	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.128+142G>T		intron	N/A	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.128+142G>T		intron	N/A	ENSP00000264657.4	P40763-1
	STAT3	ENST00000588969.5	TSL:1	c.128+142G>T		intron	N/A	ENSP00000467985.1	P40763-1
	STAT3	ENST00000404395.3	TSL:1	c.128+142G>T		intron	N/A	ENSP00000384943.3	P40763-2

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72775 AN: 151942 Hom.: 20746 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.431

GnomAD4 exome AF: 0.371 AC: 410821 AN: 1108094 Hom.: 80486 AF XY: 0.372 AC XY: 209476 AN XY: 562764

African (AFR) AF: 0.828 AC: 22033 AN: 26596

American (AMR) AF: 0.233 AC: 9495 AN: 40738

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 8417 AN: 22760

East Asian (EAS) AF: 0.417 AC: 15626 AN: 37494

South Asian (SAS) AF: 0.451 AC: 34403 AN: 76248

European-Finnish (FIN) AF: 0.381 AC: 15541 AN: 40764

Middle Eastern (MID) AF: 0.348 AC: 1225 AN: 3520

European-Non Finnish (NFE) AF: 0.351 AC: 285090 AN: 811560

Other (OTH) AF: 0.392 AC: 18991 AN: 48414

GnomAD4 genome AF: 0.479 AC: 72895 AN: 152060 Hom.: 20809 Cov.: 32 AF XY: 0.478 AC XY: 35541 AN XY: 74324

African (AFR) AF: 0.808 AC: 33523 AN: 41480

American (AMR) AF: 0.298 AC: 4546 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1317 AN: 3470

East Asian (EAS) AF: 0.417 AC: 2153 AN: 5166

South Asian (SAS) AF: 0.468 AC: 2252 AN: 4812

European-Finnish (FIN) AF: 0.385 AC: 4066 AN: 10572

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23655 AN: 67982

Other (OTH) AF: 0.438 AC: 923 AN: 2108

Alfa AF: 0.430 Hom.: 2520

Bravo AF: 0.487

Asia WGS AF: 0.543 AC: 1884 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.36
PhyloP100		0.14
PromoterAI		-0.0024	Neutral
Mutation Taster		=99/1	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: rs2306581; hg19: chr17-40500265;