rs587777629

Variant names:

• chr2-190995151-T-C
• rs587777629
• NM_007315.4:c.854A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-190995151-T-C
• chr2-190995151-T-A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV004047280: 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).". Synonymous variant affecting the same amino acid position (i.e. Q285Q) has been classified as Likely benign.

• 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
• Publications: 6 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: Illumina, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004047280: 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).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_007315.4
• PM2: Very rare variant in population databases, with high coverage
• 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 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 VariationId is 144005.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007315.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	NM_007315.4	MANE Select	c.854A>G	p.Gln285Arg	missense	Exon 10 of 25	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.890A>G	p.Gln297Arg	missense	Exon 10 of 25	NP_001371820.1
	STAT1	NM_001384886.1		c.854A>G	p.Gln285Arg	missense	Exon 10 of 25	NP_001371815.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000361099.8	TSL:1 MANE Select	c.854A>G	p.Gln285Arg	missense	Exon 10 of 25	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.854A>G	p.Gln285Arg	missense	Exon 9 of 24	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.854A>G	p.Gln285Arg	missense	Exon 10 of 23	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.28	T
Sift4G	Benign	0.56	T
Polyphen		0.0030	B
Vest4		0.77
MutPred		0.48		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
Mutation Taster		=0/100	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: rs587777629; hg19: chr2-191859877;