rs2066802

chr2-191009941-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007315.4(STAT1):c.63T>C(p.Leu21=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.410

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 333293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-191009941-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT1	NM_007315.4	c.63T>C	p.Leu21=	synonymous_variant	3/25	ENST00000361099.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT1	ENST00000361099.8	c.63T>C	p.Leu21=	synonymous_variant	3/25	1	NM_007315.4	P4

Frequencies

GnomAD3 genomes AF: 0.0704 AC: 10713 AN: 152086 Hom.: 469 Cov.: 32

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

GnomAD3 exomes AF: 0.0831 AC: 20892 AN: 251436 Hom.: 1271 AF XY: 0.0881 AC XY: 11968 AN XY: 135884

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 SAS exome AF: 0.163

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.: 31 AF XY: 0.0735 AC XY: 53467 AN XY: 727168

Gnomad4 AFR exome AF: 0.0804

Gnomad4 AMR exome AF: 0.0436

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.0365

Gnomad4 NFE exome AF: 0.0578

Gnomad4 OTH exome AF: 0.0810

GnomAD4 genome AF: 0.0705 AC: 10725 AN: 152204 Hom.: 472 Cov.: 32 AF XY: 0.0714 AC XY: 5314 AN XY: 74408

Gnomad4 AFR AF: 0.0745

Gnomad4 AMR AF: 0.0495

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0388

Gnomad4 NFE AF: 0.0589

Gnomad4 OTH AF: 0.0687

Alfa AF: 0.0632 Hom.: 426

Bravo AF: 0.0699

Asia WGS AF: 0.190 AC: 661 AN: 3478

EpiCase AF: 0.0608

EpiControl AF: 0.0604

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.9
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2066802; hg19: chr2-191874667; COSMIC: COSV100738472;