2-190995184-C-T

Variant names:

• chr2-190995184-C-T
• rs387906760
• NM_007315.4:c.821G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. 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
• Publications: 50 publications found

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 Gene-Disease associations (from GenCC):

• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, Orphanet
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• 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 CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 160354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the STAT1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 64 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 5.1492 (above the threshold of 3.09). Trascript score misZ: 7.0181 (above the threshold of 3.09). GenCC associations: The gene is linked to immunodeficiency 31B, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome.
• 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Pathogenic. Clinvar id is 30085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.821G>A	p.Arg274Gln	missense_variant	Exon 10 of 25	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.821G>A	p.Arg274Gln	missense_variant	Exon 10 of 25	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STAT1: PM1, PM2, PS3:Moderate, PS4:Moderate, PP2, PP4 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

STAT1-related disorder Pathogenic:1

-

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Dec 21, 2022

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Pathogenic	0.99	.;D;D;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;.
PhyloP100		5.0
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
Mutation Taster		=5/95	disease causing (ClinVar)

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