chr2-190995143-T-G

Position:

• chr2-190995143-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_007315.4(STAT1):​c.862A>C​(p.Thr288Pro) 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. T288A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a coiled_coil_region (size 181) in uniprot entity STAT1_HUMAN there are 33 pathogenic changes around while only 1 benign (97%) in NM_007315.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-190995143-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT1. . Gene score misZ 5.1492 (greater than the threshold 3.09). Trascript score misZ 7.0181 (greater than threshold 3.09). GenCC has associacion of gene with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT1	NM_007315.4	c.862A>C	p.Thr288Pro	missense_variant	10/25	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.862A>C	p.Thr288Pro	missense_variant	10/25	1	NM_007315.4	ENSP00000354394	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;.;.
Eigen	Benign	0.0046
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.8	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.28	B;B;D;.
Vest4		0.62
MutPred		0.54		Loss of phosphorylation at T288 (P = 0.0341);Loss of phosphorylation at T288 (P = 0.0341);Loss of phosphorylation at T288 (P = 0.0341);.;
MVP		0.81
MPC		1.7
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.92

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-191859869;