17-42313814-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_139276.3(STAT3):c.*1931A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 232,894 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (5 hom.)
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-42313814-T-C is Benign according to our data. Variant chr17-42313814-T-C is described in ClinVar as [Benign]. Clinvar id is 323212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00796 (1212/152168) while in subpopulation SAS AF= 0.0118 (57/4824). AF 95% confidence interval is 0.00936. There are 11 homozygotes in gnomad4. There are 732 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT3	NM_139276.3	c.*1931A>G		3_prime_UTR_variant	24/24	ENST00000264657.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT3	ENST00000264657.10	c.*1931A>G		3_prime_UTR_variant	24/24	1	NM_139276.3	A1

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1214 AN: 152050 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00720

GnomAD4 exome AF: 0.00544 AC: 439 AN: 80726 Hom.: 5 Cov.: 0 AF XY: 0.00584 AC XY: 217 AN XY: 37178

Gnomad4 AFR exome AF: 0.000520

Gnomad4 AMR exome AF: 0.00487

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00435

Gnomad4 FIN exome AF: 0.0328

Gnomad4 NFE exome AF: 0.00646

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.00796 AC: 1212 AN: 152168 Hom.: 11 Cov.: 32 AF XY: 0.00984 AC XY: 732 AN XY: 74392

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.00722

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0509

Gnomad4 NFE AF: 0.00660

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00900 Hom.: 0

Bravo AF: 0.00404

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgE recurrent infection syndrome 1, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	1.6
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs138326799; hg19: chr17-40465832;