2-190995185-G-C

Position:

• chr2-190995185-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_007315.4(STAT1):​c.820C>G​(p.Arg274Gly) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 19 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 chr2-190995184-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.
• PP2: Missense variant where missense usually causes diseases, STAT1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 2-190995185-G-C is Pathogenic according to our data. 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. Variant chr2-190995185-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT1	NM_007315.4	c.820C>G	p.Arg274Gly	missense_variant	10/25	ENST00000361099.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT1	ENST00000361099.8	c.820C>G	p.Arg274Gly	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/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23541320, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030083,VCV000030085, PMID:21714643,21727188, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.835, 3CNET: 0.99, PP3_P). A missense variant is a common mechanism associated with Immunodeficiency 31C (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2018

This sequence change replaces arginine with glycine at codon 274 of the STAT1 protein (p.Arg274Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Two different missense substitution at this codon (p.Arg274Gln and p.Arg274Trp) have been determined to be pathogenic (PMID: 21714643, 21727188, 22195034, 22847544, 25367169, 26604104, 26242301, 28258222). This suggests that the arginine residue is critical for STAT1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies using transfected cells have shown that this missense change causes results in delayed dephosphorylation, enhanced DNA binding, and enhanced transactivation of STAT1 after IFN-γ and IFN-α stimulation (PMID: 23541320). This variant has been reported in an individual affected with oral candidiasis and disseminated histoplasmosis (PMID: 23541320). ClinVar contains an entry for this variant (Variation ID: 160354). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	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	0.72	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.88
MutPred		0.80		Loss of MoRF binding (P = 0.0759);Loss of MoRF binding (P = 0.0759);Loss of MoRF binding (P = 0.0759);.;
MVP		0.95
MPC		2.7
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.96

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;