2-190995209-C-A

Variant names:

• chr2-190995209-C-A
• rs41473544
• NM_007315.4:c.796G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001384891.1(STAT1):​c.832G>T​(p.Val278Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V278I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT1 NM_001384891.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.630
• 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: 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: Likely_pathogenic. The variant received 9 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, 3 uncertain in NM_001384891.1
• PM2: Very rare variant in population databases, with high coverage
• 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: 6.9651 (above the threshold of 3.09). GenCC associations: The gene is linked to immunodeficiency 31B, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384891.1. 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.796G>T	p.Val266Phe	missense	Exon 10 of 25	NP_009330.1
	STAT1	NM_001384891.1		c.832G>T	p.Val278Phe	missense	Exon 10 of 25	NP_001371820.1
	STAT1	NM_001384886.1		c.796G>T	p.Val266Phe	missense	Exon 10 of 25	NP_001371815.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000361099.8	TSL:1 MANE Select	c.796G>T	p.Val266Phe	missense	Exon 10 of 25	ENSP00000354394.4
	STAT1	ENST00000409465.5	TSL:1	c.796G>T	p.Val266Phe	missense	Exon 9 of 24	ENSP00000386244.1
	STAT1	ENST00000392322.7	TSL:1	c.796G>T	p.Val266Phe	missense	Exon 10 of 23	ENSP00000376136.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.63
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.37
Sift	Benign	0.049	D
Sift4G	Uncertain	0.048	D
Polyphen		0.42	B
Vest4		0.77
MutPred		0.82		Loss of MoRF binding (P = 0.1683)
MVP		0.79
MPC		1.7
ClinPred		0.61	D
GERP RS		0.79
Varity_R		0.38
gMVP		0.97
Mutation Taster		=87/13	polymorphism

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: rs41473544; hg19: chr2-191859935;