rs41473544

Variant names:

• chr2-190995209-C-T
• rs41473544
• NM_007315.4:c.796G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-190995209-C-T
• chr2-190995209-C-A
• chr2-190995209-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_007315.4(STAT1):​c.796G>A​(p.Val266Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,894 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (15 hom.)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 0.630
• Publications: 19 publications found

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]

STAT1 Gene-Disease associations (from GenCC):

• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_007315.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014246553).
• BP6: Variant 2-190995209-C-T is Benign according to our data. Variant chr2-190995209-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 333285.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00241 (367/152142) while in subpopulation NFE AF = 0.00332 (226/68008). AF 95% confidence interval is 0.00297. There are 0 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007315.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	NM_007315.4	MANE Select	c.796G>A	p.Val266Ile	missense	Exon 10 of 25	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.832G>A	p.Val278Ile	missense	Exon 10 of 25	NP_001371820.1
	STAT1	NM_001384886.1		c.796G>A	p.Val266Ile	missense	Exon 10 of 25	NP_001371815.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000361099.8	TSL:1 MANE Select	c.796G>A	p.Val266Ile	missense	Exon 10 of 25	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.796G>A	p.Val266Ile	missense	Exon 9 of 24	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.796G>A	p.Val266Ile	missense	Exon 10 of 23	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 367 AN: 152024 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00776

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00237 AC: 597 AN: 251406 AF XY: 0.00234

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00684

Gnomad NFE exome AF: 0.00337

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00322 AC: 4705 AN: 1461752 Hom.: 15 Cov.: 31 AF XY: 0.00315 AC XY: 2292 AN XY: 727180

African (AFR) AF: 0.000358 AC: 12 AN: 33474

American (AMR) AF: 0.00103 AC: 46 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000672 AC: 58 AN: 86258

European-Finnish (FIN) AF: 0.00639 AC: 341 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00367 AC: 4083 AN: 1111938

Other (OTH) AF: 0.00243 AC: 147 AN: 60384

GnomAD4 genome AF: 0.00241 AC: 367 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.00251 AC XY: 187 AN XY: 74364

African (AFR) AF: 0.000892 AC: 37 AN: 41500

American (AMR) AF: 0.00105 AC: 16 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00776 AC: 82 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00332 AC: 226 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00255 Hom.: 3

Bravo AF: 0.00190

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (2)
1	-	1	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (2)
-	-	1	Immunodeficiency 31B (1)
-	-	1	STAT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.33	N
PhyloP100		0.63
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.29
Sift	Benign	0.69	T
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.48
MVP		0.86
MPC		1.1
ClinPred		0.0014	T
GERP RS		0.79
Varity_R		0.038
gMVP		0.73
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs41473544; hg19: chr2-191859935;