rs3830585

Variant names:

• chr17-42323632-G-GA
• rs3830585
• NM_139276.3:c.1601-8dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_139276.3(STAT3):​c.1601-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,038 control chromosomes in the GnomAD database, including 53,571 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (12220 hom., cov: 0)
  • Exomes 𝑓: 0.22 (41351 hom.)
• Consequence: STAT3 NM_139276.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.765
• Publications: 14 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 -16 ACMG points.

• BP6: Variant 17-42323632-G-GA is Benign according to our data. Variant chr17-42323632-G-GA is described in ClinVar as Benign. ClinVar VariationId is 165294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 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.1601-8dupT		splice_region intron	N/A	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.1601-8dupT		splice_region intron	N/A	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.1601-8dupT		splice_region 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.1601-8_1601-7insT		splice_region intron	N/A	ENSP00000264657.4	P40763-1
	STAT3	ENST00000588969.5	TSL:1	c.1601-8_1601-7insT		splice_region intron	N/A	ENSP00000467985.1	P40763-1
	STAT3	ENST00000404395.3	TSL:1	c.1601-8_1601-7insT		splice_region intron	N/A	ENSP00000384943.3	P40763-2

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51335 AN: 151992 Hom.: 12179 Cov.: 0

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.246 AC: 61687 AN: 250758 AF XY: 0.244

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.346

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.220 AC: 320944 AN: 1460928 Hom.: 41351 Cov.: 32 AF XY: 0.222 AC XY: 161210 AN XY: 726838

African (AFR) AF: 0.696 AC: 23278 AN: 33440

American (AMR) AF: 0.132 AC: 5892 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 7334 AN: 26136

East Asian (EAS) AF: 0.355 AC: 14069 AN: 39662

South Asian (SAS) AF: 0.318 AC: 27385 AN: 86220

European-Finnish (FIN) AF: 0.198 AC: 10566 AN: 53398

Middle Eastern (MID) AF: 0.296 AC: 1708 AN: 5766

European-Non Finnish (NFE) AF: 0.194 AC: 215372 AN: 1111290

Other (OTH) AF: 0.254 AC: 15340 AN: 60356

GnomAD4 genome AF: 0.338 AC: 51437 AN: 152110 Hom.: 12220 Cov.: 0 AF XY: 0.338 AC XY: 25095 AN XY: 74352

African (AFR) AF: 0.675 AC: 28013 AN: 41470

American (AMR) AF: 0.181 AC: 2764 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3470

East Asian (EAS) AF: 0.363 AC: 1880 AN: 5172

South Asian (SAS) AF: 0.345 AC: 1662 AN: 4820

European-Finnish (FIN) AF: 0.196 AC: 2075 AN: 10574

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13069 AN: 68004

Other (OTH) AF: 0.316 AC: 667 AN: 2112

Alfa AF: 0.248 Hom.: 1394

Bravo AF: 0.349

EpiCase AF: 0.204

EpiControl AF: 0.206

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant (1)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4014795:STAT3-related early-onset multisystem autoimmune disease (1)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function (1)
-	-	1	Hyper-IgE syndrome (1)
-	-	1	not provided (2)
-	-	1	STAT3-related early-onset multisystem autoimmune disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.77
Mutation Taster		=100/0	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: rs3830585; hg19: chr17-40475650; COSMIC: COSV52883546;