rs144812882

chr12-56356463-C-Achr12-56356463-C-Gchr12-56356463-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

The NM_005419.4(STAT2):c.109G>T(p.Val37Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V37L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: -0.776

Genes affected

STAT2 (HGNC:11363): (signal transducer and activator of transcription 2) 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. In response to interferon (IFN), this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly. The protein mediates innate antiviral activity. Mutations in this gene result in Immunodeficiency 44. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STAT2
• BP4: Computational evidence support a benign effect (MetaRNN=0.13583994).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000112 (17/152314) while in subpopulation AMR AF= 0.000719 (11/15306). AF 95% confidence interval is 0.000402. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT2	NM_005419.4	c.109G>T	p.Val37Phe	missense_variant	2/24	ENST00000314128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT2	ENST00000314128.9	c.109G>T	p.Val37Phe	missense_variant	2/24	1	NM_005419.4	P2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251294 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000903 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 12-18-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 37 of the STAT2 protein (p.Val37Phe). This variant is present in population databases (rs144812882, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with STAT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 569571). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STAT2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.99	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.069	T;T;T
Sift4G	Benign	0.062	T;T;T
Polyphen		0.86	P;.;P
Vest4		0.19
MVP		0.59
MPC		0.96
ClinPred		0.081	T
GERP RS		1.9
Varity_R		0.26
gMVP		0.19

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: rs144812882; hg19: chr12-56750247;