2-190985373-A-G

Variant names:

• chr2-190985373-A-G
• rs2280234
• NM_007315.4:c.1263+246T>C

Variant summary

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

The NM_007315.4(STAT1):​c.1263+246T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 152,170 control chromosomes in the GnomAD database, including 21,722 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 0.52 (21722 hom., cov: 33)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107
• Publications: 18 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: 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.616 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	NM_007315.4	MANE Select	c.1263+246T>C		intron	N/A	NP_009330.1
	STAT1	NM_001384891.1		c.1299+246T>C		intron	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.1263+246T>C		intron	N/A	NP_001371815.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000361099.8	TSL:1 MANE Select	c.1263+246T>C		intron	N/A	ENSP00000354394.4
	STAT1	ENST00000409465.5	TSL:1	c.1263+246T>C		intron	N/A	ENSP00000386244.1
	STAT1	ENST00000392322.7	TSL:1	c.1263+246T>C		intron	N/A	ENSP00000376136.3

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78786 AN: 152052 Hom.: 21706 Cov.: 33

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.511

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

GnomAD4 genome AF: 0.518 AC: 78825 AN: 152170 Hom.: 21722 Cov.: 33 AF XY: 0.518 AC XY: 38564 AN XY: 74404

African (AFR) AF: 0.388 AC: 16094 AN: 41496

American (AMR) AF: 0.417 AC: 6376 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1855 AN: 3472

East Asian (EAS) AF: 0.212 AC: 1099 AN: 5180

South Asian (SAS) AF: 0.469 AC: 2266 AN: 4834

European-Finnish (FIN) AF: 0.674 AC: 7146 AN: 10598

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42212 AN: 67986

Other (OTH) AF: 0.507 AC: 1070 AN: 2110

Alfa AF: 0.584 Hom.: 9132

Bravo AF: 0.494

Asia WGS AF: 0.372 AC: 1292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.19
DANN	Benign	0.19
PhyloP100		-0.11
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: rs2280234; hg19: chr2-191850099;