2-190971192-T-C

Variant names:

• chr2-190971192-T-C
• rs7575823
• NM_007315.4:c.2239-475A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007315.4(STAT1):​c.2239-475A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 152,172 control chromosomes in the GnomAD database, including 56,281 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.86 (56281 hom., cov: 31)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.893 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	NM_007315.4	MANE Select	c.2239-475A>G		intron	N/A	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.2275-475A>G		intron	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.2263-475A>G		intron	N/A	NP_001371815.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000361099.8	TSL:1 MANE Select	c.2239-475A>G		intron	N/A	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.2239-475A>G		intron	N/A	ENSP00000386244.1	P42224-1
	STAT1	ENST00000673847.1		c.2238+3638A>G		intron	N/A	ENSP00000501185.1	A0A669KBA4

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130440 AN: 152054 Hom.: 56241 Cov.: 31

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.833

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.858 AC: 130538 AN: 152172 Hom.: 56281 Cov.: 31 AF XY: 0.860 AC XY: 63951 AN XY: 74372

African (AFR) AF: 0.765 AC: 31722 AN: 41470

American (AMR) AF: 0.891 AC: 13631 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 2883 AN: 3468

East Asian (EAS) AF: 0.857 AC: 4438 AN: 5178

South Asian (SAS) AF: 0.823 AC: 3971 AN: 4824

European-Finnish (FIN) AF: 0.939 AC: 9951 AN: 10598

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.899 AC: 61129 AN: 68016

Other (OTH) AF: 0.834 AC: 1762 AN: 2112

Alfa AF: 0.858 Hom.: 36663

Bravo AF: 0.851

Asia WGS AF: 0.861 AC: 2996 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.071
DANN	Benign	0.58
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7575823; hg19: chr2-191835918;