rs56228116

Variant names:

• chr2-190985612-C-T
• rs56228116
• NM_007315.4:c.1263+7G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_007315.4(STAT1):​c.1263+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: STAT1 NM_007315.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003602
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.926
• Publications: 3 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-190985612-C-T is Benign according to our data. Variant chr2-190985612-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000545 (83/152318) while in subpopulation NFE AF = 0.00109 (74/68030). AF 95% confidence interval is 0.000888. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1263+7G>A		splice_region intron	N/A	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.1299+7G>A		splice_region intron	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.1263+7G>A		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.1263+7G>A		splice_region intron	N/A	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.1263+7G>A		splice_region intron	N/A	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.1263+7G>A		splice_region intron	N/A	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000382 AC: 96 AN: 251456 AF XY: 0.000390

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000621 AC: 908 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.000575 AC XY: 418 AN XY: 727234

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000793 AC: 882 AN: 1111982

Other (OTH) AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74470

African (AFR) AF: 0.000144 AC: 6 AN: 41564

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.000465

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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 specified (1)
-	-	1	STAT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.1
DANN	Benign	0.23
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
Splicevardb		2.0
SpliceAI score (max)		0.090		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: rs56228116; hg19: chr2-191850338;