2-190999659-A-T

Position:

• chr2-190999659-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The ENST00000361099.8(STAT1):​c.508T>A​(p.Tyr170Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT1 ENST00000361099.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.25

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 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000361099.8
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 2-190999659-A-T is Pathogenic according to our data. Variant chr2-190999659-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 30091.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-190999659-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT1	NM_007315.4	c.508T>A	p.Tyr170Asn	missense_variant	7/25	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.508T>A	p.Tyr170Asn	missense_variant	7/25	1	NM_007315.4	ENSP00000354394	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;D;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D;.
Polyphen		0.75	P;.;P;P;.;.
Vest4		0.80
MutPred		0.67		Gain of disorder (P = 0.035);Gain of disorder (P = 0.035);Gain of disorder (P = 0.035);Gain of disorder (P = 0.035);.;Gain of disorder (P = 0.035);
MVP		0.81
MPC		2.1
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906766; hg19: chr2-191864385;