2-190995184-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_007315.4(STAT1):c.821G>A(p.Arg274Gln) variant causes a missense change. 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 NM_007315.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.96

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 16 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 NM_007315.4
• 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 where missense usually causes diseases, STAT1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 2-190995184-C-T is Pathogenic according to our data. Variant chr2-190995184-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190995184-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT1	NM_007315.4	c.821G>A	p.Arg274Gln	missense_variant	10/25	ENST00000361099.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT1	ENST00000361099.8	c.821G>A	p.Arg274Gln	missense_variant	10/25	1	NM_007315.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

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	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R274Q in STAT1 (NM_007315.4) has been previously reported in affected patients (Fujiki R et al,Depner M et al). Other variants affecting this residue have been classified as disease causing. The variant has been submitted to ClinVar as Pathogenic. The p.R274Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R274Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 274 of STAT1 is conserved in all mammalian species. The nucleotide c.821 in STAT1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	STAT1: PM1, PM2, PS3:Moderate, PS4:Moderate, PP2, PP4 -

STAT1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

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

Invitae

Oct 06, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 274 of the STAT1 protein (p.Arg274Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant chronic mucocutaneous candidiasis (PMID: 21727188, 22847544, 26242301, 26604104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30085). 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: 21727188, 26242301, 28258222). This variant disrupts the p.Arg274 amino acid residue in STAT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21714643, 21727188, 25367169, 26604104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Pathogenic	3.0	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.037	D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.66
MutPred		0.76		Loss of MoRF binding (P = 0.0768);Loss of MoRF binding (P = 0.0768);Loss of MoRF binding (P = 0.0768);.;
MVP		0.88
MPC		2.5
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.90

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: rs387906760; hg19: chr2-191859910; COSMIC: COSV61190263; COSMIC: COSV61190263;