2-190995151-T-C

Position:

• chr2-190995151-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_007315.4(STAT1):​c.854A>G​(p.Gln285Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.13

Genes affected

STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) 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. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

STAT1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a coiled_coil_region (size 181) in uniprot entity STAT1_HUMAN there are 33 pathogenic changes around while only 1 benign (97%) in NM_007315.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT1. . Gene score misZ 5.1492 (greater than the threshold 3.09). Trascript score misZ 7.0181 (greater than threshold 3.09). GenCC has associacion of gene with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B.
• PP5: Variant 2-190995151-T-C is Pathogenic according to our data. Variant chr2-190995151-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 144005.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-190995151-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT1	NM_007315.4	c.854A>G	p.Gln285Arg	missense_variant	10/25	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.854A>G	p.Gln285Arg	missense_variant	10/25	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The STAT1 c.854A>G(p.Gln285Arg) variant has been reported in individuals affected with chronic mucocutaneous candidiasis (Soltesz et al., 2013). Experimental studies have shown that c.854 A>G (p.Gln285Arg) variant affecting the coiled-coil domain (CCD) of STAT1 is GOF. Upon stimulation with IFN-γ, cells transfected with the Q285R allele responded two to three times more strongly than those transfected with the WT or Y701C alleles (Soltesz et al., 2013). The amino acid Gln at position 285 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic with a status of no assertion criteria provided. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Gln285Arg in STAT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Gln285Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M;M;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0030	B;B;D;.
Vest4		0.77
MutPred		0.48		Gain of phosphorylation at T288 (P = 0.1078);Gain of phosphorylation at T288 (P = 0.1078);Gain of phosphorylation at T288 (P = 0.1078);.;
MVP		0.89
MPC		1.4
ClinPred		0.82	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.82

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: rs587777629; hg19: chr2-191859877;