rs387906758

Positions:

• chr2-190995185-G-A
• chr2-190995185-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000361099.8(STAT1):​c.820C>T​(p.Arg274Trp) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT1 ENST00000361099.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a coiled_coil_region (size 181) in uniprot entity STAT1_HUMAN there are 67 pathogenic changes around while only 4 benign (94%) in ENST00000361099.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-190995185-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 2-190995185-G-A is Pathogenic according to our data. Variant chr2-190995185-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190995185-G-A is described in Lovd as [Pathogenic]. Variant chr2-190995185-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT1	NM_007315.4	c.820C>T	p.Arg274Trp	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.820C>T	p.Arg274Trp	missense_variant	10/25	1	NM_007315.4	ENSP00000354394	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030083). The variant has been previously reported as de novo in at least one similarly affected unrelated individual (3billion dataset). and to co-segregate with the disease in multiple similarly affected individuals from unrelated families (PMID:21727188). Different missense changes at the same codon (p.Arg274Gln, p.Arg274Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030085, VCV000160354). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Aug 21, 2012	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -

STAT1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2023

The STAT1 c.820C>T variant is predicted to result in the amino acid substitution p.Arg274Trp. This variant has been reported in the heterozygous state in individuals with chronic mucocutaneous candidiasis and immunodeficiency (Tables S9 and S10, van de Veerdonk et al. 2011. PubMed ID: 21714643; Depner et al. 2016. PubMed ID: 26604104; Patient S103, Baxter et al. 2021. PubMed ID: 33864888). Of note, this variant segregated with disease in one family, being present in three affected family members and was not identified in nine unaffected individuals (Tables S9 and S10, van de Veerdonk et al. 2011. PubMed ID: 21714643). Of note, other variants impacting p.Arg274 have also been reported in individuals with mucocutaneous candidiasis or disseminated histoplasmosis (p.Arg274Gly and p.Arg274Gln; Liu. 2011. PubMed ID: 21727188; Patient 5, Sampaio et al. 2013. PubMed ID: 23541320; Depner et al. 2016. PubMed ID: 26604104). Of note, all of these variants impacting p.Arg274 have been reported to be gain-of-function variants. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/30083/). This variant is interpreted as pathogenic. -

Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 274 of the STAT1 protein (p.Arg274Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic mucocutaneous candidiasis (PMID: 21714643, 21727188, 25326637, 25367169, 26604104). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30083). 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. Experimental studies have shown that this missense change affects STAT1 function (PMID: 21714643, 22195034, 26255980). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.0	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.78
MutPred		0.81		Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);.;
MVP		0.86
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.71
gMVP		0.93

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: rs387906758; hg19: chr2-191859911;