rs6751855

Variant names:

• chr2-191020045-G-A
• rs6751855
• ENST00000454414.5:c.-2+155C>T

Variant summary

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

The ENST00000454414.5(STAT1):​c.-2+155C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 152,090 control chromosomes in the GnomAD database, including 14,683 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 0.39 (14683 hom., cov: 33)
• Consequence: STAT1 ENST00000454414.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.219
• Publications: 12 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=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000454414.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000454414.5	TSL:4	c.-2+155C>T		intron	N/A	ENSP00000411398.1
	STAT1	ENST00000432058.1	TSL:4	c.-156+713C>T		intron	N/A	ENSP00000416019.1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59533 AN: 151972 Hom.: 14680 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.379

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

GnomAD4 genome AF: 0.391 AC: 59540 AN: 152090 Hom.: 14683 Cov.: 33 AF XY: 0.395 AC XY: 29403 AN XY: 74368

African (AFR) AF: 0.109 AC: 4504 AN: 41482

American (AMR) AF: 0.416 AC: 6355 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1294 AN: 3466

East Asian (EAS) AF: 0.154 AC: 796 AN: 5174

South Asian (SAS) AF: 0.452 AC: 2180 AN: 4822

European-Finnish (FIN) AF: 0.593 AC: 6272 AN: 10576

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36770 AN: 67980

Other (OTH) AF: 0.378 AC: 798 AN: 2112

Alfa AF: 0.425 Hom.: 12199

Bravo AF: 0.361

Asia WGS AF: 0.301 AC: 1042 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.7
DANN	Benign	0.75
PhyloP100		0.22
PromoterAI		0.0019	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6751855; hg19: chr2-191884771;