2-191131792-T-C

Variant names:

• chr2-191131792-T-C
• rs1551443
• NM_003151.4:c.273+14821A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003151.4(STAT4):​c.273+14821A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,340,730 control chromosomes in the GnomAD database, including 274,272 homozygotes. 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 0.63 (31240 hom., cov: 32)
  • Exomes 𝑓: 0.64 (243032 hom.)
• Consequence: STAT4 NM_003151.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.370
• Publications: 26 publications found

Genes affected

STAT4 (HGNC:11365): (signal transducer and activator of transcription 4) The protein encoded by this gene is a member of the STAT family of transcription factors. 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 essential for mediating responses to IL12 in lymphocytes, and regulating the differentiation of T helper cells. Mutations in this gene may be associated with systemic lupus erythematosus and rheumatoid arthritis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Aug 2011]

STAT4 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
• disabling pansclerotic morphea of childhood

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000300654 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT4	NM_003151.4	c.273+14821A>G		intron_variant	Intron 3 of 23	ENST00000392320.7	NP_003142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT4	ENST00000392320.7	c.273+14821A>G		intron_variant	Intron 3 of 23	1	NM_003151.4	ENSP00000376134.2

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96014 AN: 151296 Hom.: 31203 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.626

GnomAD2 exomes AF: 0.677 AC: 23378 AN: 34520 AF XY: 0.677

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.781

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.681

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.645

GnomAD4 exome AF: 0.637 AC: 757042 AN: 1189316 Hom.: 243032 Cov.: 35 AF XY: 0.638 AC XY: 366709 AN XY: 574648

African (AFR) AF: 0.576 AC: 13765 AN: 23904

American (AMR) AF: 0.738 AC: 7989 AN: 10818

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 9818 AN: 16676

East Asian (EAS) AF: 0.763 AC: 21335 AN: 27978

South Asian (SAS) AF: 0.740 AC: 32295 AN: 43664

European-Finnish (FIN) AF: 0.723 AC: 30268 AN: 41874

Middle Eastern (MID) AF: 0.540 AC: 2635 AN: 4882

European-Non Finnish (NFE) AF: 0.627 AC: 608600 AN: 971406

Other (OTH) AF: 0.631 AC: 30337 AN: 48114

GnomAD4 genome AF: 0.635 AC: 96097 AN: 151414 Hom.: 31240 Cov.: 32 AF XY: 0.642 AC XY: 47528 AN XY: 73982

African (AFR) AF: 0.576 AC: 23539 AN: 40874

American (AMR) AF: 0.697 AC: 10628 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2045 AN: 3470

East Asian (EAS) AF: 0.714 AC: 3687 AN: 5164

South Asian (SAS) AF: 0.751 AC: 3619 AN: 4818

European-Finnish (FIN) AF: 0.720 AC: 7619 AN: 10584

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42758 AN: 67946

Other (OTH) AF: 0.628 AC: 1319 AN: 2100

Alfa AF: 0.625 Hom.: 127018

Bravo AF: 0.628

Asia WGS AF: 0.749 AC: 2602 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		0.37
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: rs1551443; hg19: chr2-191996518; COSMIC: COSV107432419;