2-190995209-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_007315.4(STAT1):c.796G>A(p.Val266Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,894 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 15 hom. )

Consequence

STAT1
NM_007315.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:7

Conservation

PhyloP100: 0.630

Publications

19 publications found

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 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)

STAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_007315.4

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.014246553).

BP6

Variant 2-190995209-C-T is Benign according to our data. Variant chr2-190995209-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 333285.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00241 (367/152142) while in subpopulation NFE AF = 0.00332 (226/68008). AF 95% confidence interval is 0.00297. There are 0 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4 link	c.796G>A	p.Val266Ile	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 link	c.796G>A	p.Val266Ile	missense_variant	Exon 10 of 25	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00776

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00332

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00237

AC:

597

AN:

251406

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00684

Gnomad NFE exome

AF:

0.00337

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00322

AC:

4705

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00315

AC XY:

2292

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33474

American (AMR)

AF:

0.00103

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000672

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00639

AC:

341

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00367

AC:

4083

AN:

1111938

Other (OTH)

AF:

0.00243

AC:

147

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

239

478

716

955

1194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00241

AC:

367

AN:

152142

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000892

AC:

AN:

41500

American (AMR)

AF:

0.00105

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00776

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00332

AC:

226

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00190

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

STAT1: PP2, BP4, BS3:Supporting, BS2 -

Jun 19, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Pathogenic:1Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 04, 2018

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

Uncertain:1Benign:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

STAT1 NM_007315.3 exon 10 p.Val266Ile (c.796G>A): This variant has been reported in the literature as a heterozygous variant in at least 8 individuals with varying [inconsistent?] immunodeficiency phenotypes (Uzel 2013 PMID:23534974, Mork 2015 PMID:26513235, Remaschi 2015 PMID:26162368, Szymanski 2015 PMID:26038974, Depner 2016 PMID:26604104, Rae 2018 PMID:29077208). This variant is present in 0.6% (175/25748) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-191859935-C-T) and is present in ClinVar with conflicting interpretations ranging from likely benign to pathogenic (Variation ID:333285). Functional studies are also conflicting; one study using flow cytometric anaylsis showed a significant increase in STAT1 phosphorylation with this variant compared to the wildtype, which is consistent with a gain of function effect (Uzel 2013 PMID:23534974). However, a second study using similar methodology showed no evidence for hyperphosphorylation of STAT1 with this variant (Depner 2016 PMID:26604104). This variant amino acid Isoleucine (Ile) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

STAT1-related disorder

Benign:1

Jun 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency 31B

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Uncertain

0.58

D;D;.;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.88

.;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.33

N;N;N;.

PhyloP100

0.63

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.39

N;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.68

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.48

MVP

0.86

MPC

1.1

ClinPred

0.0014

GERP RS

0.79

Varity_R

0.038

gMVP

0.73

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over