rs2066804

Variant names:

• chr2-190977033-G-A
• rs2066804
• NM_007315.4:c.1874-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-190977033-G-A
• chr2-190977033-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007315.4(STAT1):​c.1874-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,014 control chromosomes in the GnomAD database, including 51,865 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4048 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47817 hom.)
• Consequence: STAT1 NM_007315.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003493
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.225
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-190977033-G-A is Benign according to our data. Variant chr2-190977033-G-A is described in ClinVar as Benign. ClinVar VariationId is 333264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

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.1874-8C>T		splice_region intron	N/A	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.1910-8C>T		splice_region intron	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.1874-8C>T		splice_region intron	N/A	NP_001371815.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000361099.8	TSL:1 MANE Select	c.1874-8C>T		splice_region intron	N/A	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.1874-8C>T		splice_region intron	N/A	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.1874-8C>T		splice_region intron	N/A	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33772 AN: 151822 Hom.: 4051 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.226 AC: 56832 AN: 250966 AF XY: 0.229

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.446

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.249 AC: 364129 AN: 1461074 Hom.: 47817 Cov.: 34 AF XY: 0.248 AC XY: 179958 AN XY: 726864

African (AFR) AF: 0.171 AC: 5733 AN: 33472

American (AMR) AF: 0.117 AC: 5250 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 6409 AN: 26124

East Asian (EAS) AF: 0.487 AC: 19323 AN: 39690

South Asian (SAS) AF: 0.176 AC: 15216 AN: 86244

European-Finnish (FIN) AF: 0.236 AC: 12609 AN: 53394

Middle Eastern (MID) AF: 0.213 AC: 1230 AN: 5764

European-Non Finnish (NFE) AF: 0.255 AC: 283746 AN: 1111306

Other (OTH) AF: 0.242 AC: 14613 AN: 60356

GnomAD4 genome AF: 0.222 AC: 33767 AN: 151940 Hom.: 4048 Cov.: 32 AF XY: 0.220 AC XY: 16341 AN XY: 74250

African (AFR) AF: 0.171 AC: 7088 AN: 41434

American (AMR) AF: 0.170 AC: 2589 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3468

East Asian (EAS) AF: 0.450 AC: 2328 AN: 5172

South Asian (SAS) AF: 0.183 AC: 877 AN: 4804

European-Finnish (FIN) AF: 0.244 AC: 2578 AN: 10552

Middle Eastern (MID) AF: 0.193 AC: 56 AN: 290

European-Non Finnish (NFE) AF: 0.245 AC: 16663 AN: 67944

Other (OTH) AF: 0.213 AC: 450 AN: 2110

Alfa AF: 0.234 Hom.: 6938

Bravo AF: 0.213

Asia WGS AF: 0.293 AC: 1019 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.80
DANN	Benign	0.46
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0040
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: rs2066804; hg19: chr2-191841759; COSMIC: COSV63116392; COSMIC: COSV63116392;