rs587777628

chr2-190999630-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_007315.4(STAT1):c.537C>A(p.Asn179Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N179S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.188

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_007315.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STAT1
• PP5: Variant 2-190999630-G-T is Pathogenic according to our data. Variant chr2-190999630-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 144004.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-190999630-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2626174).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT1	NM_007315.4	c.537C>A	p.Asn179Lys	missense_variant	7/25	ENST00000361099.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT1	ENST00000361099.8	c.537C>A	p.Asn179Lys	missense_variant	7/25	1	NM_007315.4	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

Sep 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D;D;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.84	D;D;D;D;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.41	T;D;T;T;T;D
Sift4G	Benign	0.35	T;T;T;T;T;.
Polyphen		0.0040	B;.;B;P;.;.
Vest4		0.60
MutPred		0.49		Gain of ubiquitination at N179 (P = 0.0039);Gain of ubiquitination at N179 (P = 0.0039);Gain of ubiquitination at N179 (P = 0.0039);Gain of ubiquitination at N179 (P = 0.0039);.;Gain of ubiquitination at N179 (P = 0.0039);
MVP		0.72
MPC		1.5
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.27
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs587777628; hg19: chr2-191864356;