NM_007315.4:c.373-726G>A

Variant names:

• chr2-191001889-C-T
• rs11677408
• NM_007315.4:c.373-726G>A

Variant summary

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

The NM_007315.4(STAT1):​c.373-726G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 152,142 control chromosomes in the GnomAD database, including 317 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 0.058 (317 hom., cov: 32)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 5 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.373-726G>A		intron_variant	Intron 5 of 24	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.373-726G>A		intron_variant	Intron 5 of 24	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8819 AN: 152024 Hom.: 317 Cov.: 32

Gnomad AFR AF: 0.0857

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0440

Gnomad OTH AF: 0.0489

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

GnomAD4 genome AF: 0.0580 AC: 8829 AN: 152142 Hom.: 317 Cov.: 32 AF XY: 0.0569 AC XY: 4234 AN XY: 74364

African (AFR) AF: 0.0855 AC: 3548 AN: 41480

American (AMR) AF: 0.0370 AC: 565 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 174 AN: 3470

East Asian (EAS) AF: 0.109 AC: 566 AN: 5176

South Asian (SAS) AF: 0.109 AC: 526 AN: 4814

European-Finnish (FIN) AF: 0.0291 AC: 308 AN: 10598

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0440 AC: 2994 AN: 68006

Other (OTH) AF: 0.0488 AC: 103 AN: 2110

Alfa AF: 0.0510 Hom.: 162

Bravo AF: 0.0577

Asia WGS AF: 0.105 AC: 367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.71
DANN	Benign	0.66
PhyloP100		-1.1
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: rs11677408; hg19: chr2-191866615;