rs3024839

chr2-191076256-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_003151.4(STAT4):c.343A>G(p.Ile115Val) variant causes a missense change. The variant allele was found at a frequency of 0.000509 in 1,613,904 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: STAT4 NM_003151.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.83

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, STAT4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011779964).
• BP6: Variant 2-191076256-T-C is Benign according to our data. Variant chr2-191076256-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 741427.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 377 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT4	NM_003151.4	c.343A>G	p.Ile115Val	missense_variant	4/24	ENST00000392320.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT4	ENST00000392320.7	c.343A>G	p.Ile115Val	missense_variant	4/24	1	NM_003151.4	P1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152070 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000441

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000678 AC: 170 AN: 250850 Hom.: 0 AF XY: 0.000531 AC XY: 72 AN XY: 135552

Gnomad AFR exome AF: 0.00978

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000301 AC: 440 AN: 1461716 Hom.: 1 Cov.: 30 AF XY: 0.000253 AC XY: 184 AN XY: 727150

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152188 Hom.: 2 Cov.: 30 AF XY: 0.00237 AC XY: 176 AN XY: 74406

Gnomad4 AFR AF: 0.00865

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.00315

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000774 AC: 94

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.86	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;T
Polyphen		0.90	P;P;.
Vest4		0.31
MVP		0.45
MPC		1.4
ClinPred		0.079	T
GERP RS		4.0
Varity_R		0.39
gMVP		0.24

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: rs3024839; hg19: chr2-191940982;