dbSNP rs2066802: STAT1:p.Leu21Leu (chr2-191009941-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_007315.4(STAT1):c.63T>C(p.Leu21Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.07 in 1,613,936 control chromosomes in the GnomAD database, including 5,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.070 ( 472 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4868 hom. )

Consequence

STAT1
NM_007315.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.410

Publications

30 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: 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

STAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 2-191009941-A-G is Benign according to our data. Variant chr2-191009941-A-G is described in ClinVar as Benign. ClinVar VariationId is 333293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.41 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

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	UniProt
STAT1	NM_007315.4	MANE Select	c.63T>C	p.Leu21Leu	synonymous	Exon 3 of 25	NP_009330.1	P42224-1
STAT1	NM_001384891.1		c.63T>C	p.Leu21Leu	synonymous	Exon 3 of 25	NP_001371820.1
STAT1	NM_001384886.1		c.63T>C	p.Leu21Leu	synonymous	Exon 3 of 25	NP_001371815.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STAT1	ENST00000361099.8	TSL:1 MANE Select	c.63T>C	p.Leu21Leu	synonymous	Exon 3 of 25	ENSP00000354394.4	P42224-1
STAT1	ENST00000409465.5	TSL:1	c.63T>C	p.Leu21Leu	synonymous	Exon 2 of 24	ENSP00000386244.1	P42224-1
STAT1	ENST00000392322.7	TSL:1	c.63T>C	p.Leu21Leu	synonymous	Exon 3 of 23	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes

AF:

0.0704

AC:

10713

AN:

152086

Hom.:

469

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0743

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0496

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.217

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.0388

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0589

Gnomad OTH

AF:

0.0684

GnomAD2 exomes

AF:

0.0831

AC:

20892

AN:

251436

AF XY:

0.0881

show subpopulations

Gnomad AFR exome

AF:

0.0762

Gnomad AMR exome

AF:

0.0419

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.224

Gnomad FIN exome

AF:

0.0340

Gnomad NFE exome

AF:

0.0597

Gnomad OTH exome

AF:

0.0795

GnomAD4 exome

AF:

0.0700

AC:

102293

AN:

1461732

Hom.:

4868

Cov.:

AF XY:

0.0735

AC XY:

53467

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0804

AC:

2693

AN:

33476

American (AMR)

AF:

0.0436

AC:

1950

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2771

AN:

26132

East Asian (EAS)

AF:

0.226

AC:

8984

AN:

39678

South Asian (SAS)

AF:

0.163

AC:

14085

AN:

86248

European-Finnish (FIN)

AF:

0.0365

AC:

1949

AN:

53416

Middle Eastern (MID)

AF:

0.119

AC:

686

AN:

5766

European-Non Finnish (NFE)

AF:

0.0578

AC:

64286

AN:

1111904

Other (OTH)

AF:

0.0810

AC:

4889

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

5219

10438

15657

20876

26095

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2566

5132

7698

10264

12830

<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:

0.0705

AC:

10725

AN:

152204

Hom.:

472

Cov.:

AF XY:

0.0714

AC XY:

5314

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0745

AC:

3094

AN:

41526

American (AMR)

AF:

0.0495

AC:

758

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

358

AN:

3470

East Asian (EAS)

AF:

0.217

AC:

1122

AN:

5166

South Asian (SAS)

AF:

0.157

AC:

756

AN:

4814

European-Finnish (FIN)

AF:

0.0388

AC:

412

AN:

10606

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0589

AC:

4007

AN:

68000

Other (OTH)

AF:

0.0687

AC:

145

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

507

1014

1520

2027

2534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0631

Hom.:

522

Bravo

AF:

0.0699

Asia WGS

AF:

0.190

AC:

661

AN:

3478

EpiCase

AF:

0.0608

EpiControl

AF:

0.0604

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (1)

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.9

(source)

DANN

Benign

0.76

PhyloP100

-0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over