17-42337521-G-A

Variant names:

• chr17-42337521-G-A
• rs17882069
• NM_139276.3:c.711C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_139276.3(STAT3):​c.711C>T​(p.Asp237Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,138 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (11 hom.)
• Consequence: STAT3 NM_139276.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.513
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-42337521-G-A is Benign according to our data. Variant chr17-42337521-G-A is described in ClinVar as Benign. ClinVar VariationId is 36793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.513 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00646 (984/152244) while in subpopulation AFR AF = 0.0224 (931/41528). AF 95% confidence interval is 0.0212. There are 13 homozygotes in GnomAd4. There are 477 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 984 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.711C>T	p.Asp237Asp	synonymous	Exon 8 of 24	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.711C>T	p.Asp237Asp	synonymous	Exon 8 of 24	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.711C>T	p.Asp237Asp	synonymous	Exon 8 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.711C>T	p.Asp237Asp	synonymous	Exon 8 of 24	ENSP00000264657.4	P40763-1
	STAT3	ENST00000588969.5	TSL:1	c.711C>T	p.Asp237Asp	synonymous	Exon 8 of 24	ENSP00000467985.1	P40763-1
	STAT3	ENST00000404395.3	TSL:1	c.711C>T	p.Asp237Asp	synonymous	Exon 8 of 24	ENSP00000384943.3	P40763-2

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 985 AN: 152128 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00162 AC: 407 AN: 251422 AF XY: 0.00119

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000612 AC: 894 AN: 1461894 Hom.: 11 Cov.: 32 AF XY: 0.000542 AC XY: 394 AN XY: 727248

African (AFR) AF: 0.0208 AC: 696 AN: 33480

American (AMR) AF: 0.00139 AC: 62 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1112012

Other (OTH) AF: 0.00119 AC: 72 AN: 60396

GnomAD4 genome AF: 0.00646 AC: 984 AN: 152244 Hom.: 13 Cov.: 32 AF XY: 0.00641 AC XY: 477 AN XY: 74434

African (AFR) AF: 0.0224 AC: 931 AN: 41528

American (AMR) AF: 0.00216 AC: 33 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00293 Hom.: 3

Bravo AF: 0.00710

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant (1)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function (1)
-	-	1	STAT3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.91
DANN	Benign	0.90
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	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: rs17882069; hg19: chr17-40489539;