rs3024839

Variant names:

• chr2-191076256-T-C
• rs3024839
• NM_003151.4:c.343A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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 (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.83
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• 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 VariationId is 741427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 381 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003151.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT4	NM_003151.4	MANE Select	c.343A>G	p.Ile115Val	missense	Exon 4 of 24	NP_003142.1
	STAT4	NM_001243835.2		c.343A>G	p.Ile115Val	missense	Exon 4 of 24	NP_001230764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT4	ENST00000392320.7	TSL:1 MANE Select	c.343A>G	p.Ile115Val	missense	Exon 4 of 24	ENSP00000376134.2
	STAT4	ENST00000358470.8	TSL:1	c.343A>G	p.Ile115Val	missense	Exon 4 of 24	ENSP00000351255.4
	STAT4	ENST00000450994.2	TSL:1	c.343A>G	p.Ile115Val	missense	Exon 5 of 25	ENSP00000412397.2

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

GnomAD2 exomes AF: 0.000678 AC: 170 AN: 250850 AF XY: 0.000531

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 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

African (AFR) AF: 0.0111 AC: 372 AN: 33468

American (AMR) AF: 0.000358 AC: 16 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111900

Other (OTH) AF: 0.000729 AC: 44 AN: 60394

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

African (AFR) AF: 0.00865 AC: 359 AN: 41524

American (AMR) AF: 0.000850 AC: 13 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00108 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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.90	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
Mutation Taster		=96/4	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: rs3024839; hg19: chr2-191940982;