2-190995207-AAC-GAT

Variant names:

• chr2-190995207-AAC-GAT
• NM_007315.4:c.796_798delGTTinsATC
• STAT1 p.Val266Ile

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_007315.4(STAT1):​c.796_798delGTTinsATC​(p.Val266Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.06
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_007315.4
• PP2: Missense variant in the STAT1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 64 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 5.1492 (above the threshold of 3.09). Trascript score misZ: 7.0181 (above the threshold of 3.09). GenCC associations: The gene is linked to Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B.

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.796_798delGTTinsATC	p.Val266Ile	missense	N/A	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.832_834delGTTinsATC	p.Val278Ile	missense	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.796_798delGTTinsATC	p.Val266Ile	missense	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.796_798delGTTinsATC	p.Val266Ile	missense	N/A	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.796_798delGTTinsATC	p.Val266Ile	missense	N/A	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.796_798delGTTinsATC	p.Val266Ile	missense	N/A	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-191859933;