2-191031018-T-C

Position:

• chr2-191031018-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003151.4(STAT4):​c.2174A>G​(p.Tyr725Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT4 NM_003151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

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-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT4. . Gene score misZ 2.7415 (greater than the threshold 3.09). Trascript score misZ 3.1959 (greater than threshold 3.09). GenCC has associacion of gene with disabling pansclerotic morphea of childhood.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT4	NM_003151.4	c.2174A>G	p.Tyr725Cys	missense_variant	23/24	ENST00000392320.7	NP_003142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT4	ENST00000392320.7	c.2174A>G	p.Tyr725Cys	missense_variant	23/24	1	NM_003151.4	ENSP00000376134.2
STAT4	ENST00000358470.8	c.2174A>G	p.Tyr725Cys	missense_variant	23/24	1		ENSP00000351255.4
STAT4-AS1	ENST00000429796.1	n.268T>C		non_coding_transcript_exon_variant	1/2	2
STAT4-AS1	ENST00000456176.5	n.164T>C		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 725 of the STAT4 protein (p.Tyr725Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STAT4-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.99	D;D
Vest4		0.81
MutPred		0.38		Loss of phosphorylation at Y725 (P = 0.0081);Loss of phosphorylation at Y725 (P = 0.0081);
MVP		0.90
MPC		1.8
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.25
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-191895744;