2-190987050-A-T

Variant names:

• chr2-190987050-A-T
• rs55891000
• NM_007315.4:c.1116T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_007315.4(STAT1):​c.1116T>A​(p.Asn372Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127

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 3 ACMG points.

• 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.1116T>A	p.Asn372Lys	missense_variant	Exon 13 of 25	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.1116T>A	p.Asn372Lys	missense_variant	Exon 13 of 25	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.72
DEOGEN2	Uncertain	0.64	D;D;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.3	L;L;L;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.85	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.80	T;T;T;T
Sift4G	Benign	0.91	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.68
MutPred		0.35		Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);.;
MVP		0.62
MPC		1.4
ClinPred		0.26	T
GERP RS		-5.0
Varity_R		0.27
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs55891000; hg19: chr2-191851776;