rs387906759

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_007315.4(STAT1):c.800C>T(p.Ala267Val) 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 (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

STAT1
NM_007315.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.56

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a coiled_coil_region (size 181) in uniprot entity STAT1_HUMAN there are 33 pathogenic changes around while only 1 benign (97%) 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 2-190995205-G-A is Pathogenic according to our data. Variant chr2-190995205-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190995205-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4 link	c.800C>T	p.Ala267Val	missense_variant	Exon 10 of 25	ENST00000361099.8	NP_009330.1	P42224-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8 link	c.800C>T	p.Ala267Val	missense_variant	Exon 10 of 25	1	NM_007315.4	ENSP00000354394.4		P42224-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in unrelated individuals with autosomal dominant STAT1-related immunodeficiency in the published literature (PMID: 24343863, 21714643, 26604104, 28427548); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28161409, 34619682, 26494717, 26255980, 28815025, 28427548, 26604104, 21714643, 30187709, 32146551, 32888943, 34738677, 35753512, 35840326, 34390440, 32009323, 24343863, 23541320) -

Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

Pathogenic:2

Jun 21, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP1 strong, PP2 supporting -

Jun 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 267 of the STAT1 protein (p.Ala267Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant chronic mucocutaneous candidiasis (PMID: 21714643, 23709754, 24343863, 26255980, 26494717, 26604104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30084). 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: 23541320, 26255980). For these reasons, this variant has been classified as Pathogenic. -

Immunodeficiency 31B

Pathogenic:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Pathogenic:1

Sep 12, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a pathogenic variant with gain-of-function disease mechanisms [PMID 21714643, 28427548, 28161409, 26604104, 28815025, 24343863, 26494717, 23541320, 26255980] -

Chronic mucocutaneous candidiasis

Pathogenic:1

May 04, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala267Val variant in STAT1 has been reported in >10 individuals with chron ic mucocutaneous candidiasis (CMC) and segregated with disease in 16 individuals from 9 families (Liu 2011, van de Veerdonk 2011, Sampaio 2013, Mizoguchi 2014, Nielsen 2015, Zheng 2015, Depner 2016, Breuer 2017, Dadak 2017). It was absent f rom large population studies. Additionally, in vitro functional studies support a pathogenic role (Sampaio 2013, Mizoguchi 2014, Zheng 2015). In summary, the p. Ala267Val variant meets criteria to be classified as pathogenic for CMC in an au tosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong; PM2; PS4_Moderat e; PP3; PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.1

M;M;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.047

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.86

MutPred

0.76

Loss of catalytic residue at A267 (P = 0.0958);Loss of catalytic residue at A267 (P = 0.0958);Loss of catalytic residue at A267 (P = 0.0958);.;

MVP

0.91

MPC

2.5

ClinPred

0.97

GERP RS

5.7

Varity_R

0.76

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over