chr2-190985840-T-C

Variant names:

• chr2-190985840-T-C
• rs2280233
• NM_007315.4:c.1222-180A>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.1222-180A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,064 control chromosomes in the GnomAD database, including 12,202 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 0.38 (12202 hom., cov: 33)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• Publications: 15 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.473 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.1222-180A>G		intron	N/A	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.1258-180A>G		intron	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.1222-180A>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.1222-180A>G		intron	N/A	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.1222-180A>G		intron	N/A	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.1222-180A>G		intron	N/A	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57856 AN: 151944 Hom.: 12195 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.381 AC: 57863 AN: 152064 Hom.: 12202 Cov.: 33 AF XY: 0.383 AC XY: 28454 AN XY: 74332

African (AFR) AF: 0.243 AC: 10101 AN: 41508

American (AMR) AF: 0.294 AC: 4487 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1239 AN: 3466

East Asian (EAS) AF: 0.139 AC: 719 AN: 5176

South Asian (SAS) AF: 0.392 AC: 1889 AN: 4816

European-Finnish (FIN) AF: 0.546 AC: 5774 AN: 10570

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32440 AN: 67932

Other (OTH) AF: 0.362 AC: 763 AN: 2108

Alfa AF: 0.417 Hom.: 38534

Bravo AF: 0.352

Asia WGS AF: 0.263 AC: 914 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.24
PhyloP100		-0.32
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: rs2280233; hg19: chr2-191850566; COSMIC: COSV63115547;