2-190984316-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting

The NM_007315.4(STAT1):c.1341C>A(p.Asp447Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

STAT1
NM_007315.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.521

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

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=0.13091093).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000112 (17/152216) while in subpopulation SAS AF = 0.000623 (3/4818). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STAT1	NM_007315.4	MANE Select	c.1341C>A	p.Asp447Glu	missense	Exon 16 of 25	NP_009330.1
STAT1	NM_001384891.1		c.1377C>A	p.Asp459Glu	missense	Exon 16 of 25	NP_001371820.1
STAT1	NM_001384886.1		c.1341C>A	p.Asp447Glu	missense	Exon 16 of 25	NP_001371815.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STAT1	ENST00000361099.8	TSL:1 MANE Select	c.1341C>A	p.Asp447Glu	missense	Exon 16 of 25	ENSP00000354394.4
STAT1	ENST00000409465.5	TSL:1	c.1341C>A	p.Asp447Glu	missense	Exon 15 of 24	ENSP00000386244.1
STAT1	ENST00000392322.7	TSL:1	c.1341C>A	p.Asp447Glu	missense	Exon 16 of 23	ENSP00000376136.3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000155

AC:

AN:

251456

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000129

AC:

189

AN:

1461354

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000417

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000115

AC:

128

AN:

1111532

Other (OTH)

AF:

0.000248

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000112

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41512

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000134

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Identified as a homozygous variant a patient with severe encephalopathy who also harbored variants in additional genes in published literature (Granzow et al., 2015); This variant is associated with the following publications: (PMID: 26050939)

Jan 24, 2024

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Aug 15, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

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

Uncertain:1

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 447 of the STAT1 protein (p.Asp447Glu). This variant is present in population databases (rs140351189, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with STAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 333273). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.71

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.2

PhyloP100

0.52

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.1

REVEL

Benign

0.29

Sift

Benign

0.28

Sift4G

Benign

0.41

Polyphen

0.0010

Vest4

0.12

MutPred

0.52

Loss of sheet (P = 0.1398)

MVP

0.65

MPC

1.2

ClinPred

0.031

GERP RS

3.0

Varity_R

0.15

gMVP

0.78

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over