chr2-190977153-A-G

Variant names:

• chr2-190977153-A-G
• rs7597768
• NM_007315.4:c.1874-128T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007315.4(STAT1):​c.1874-128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 862,766 control chromosomes in the GnomAD database, including 25,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4100 hom., cov: 32)
  • Exomes 𝑓: 0.23 (21464 hom.)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.350
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-190977153-A-G is Benign according to our data. Variant chr2-190977153-A-G is described in ClinVar as Benign. ClinVar VariationId is 1174479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 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.1874-128T>C		intron	N/A	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.1910-128T>C		intron	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.1874-128T>C		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.1874-128T>C		intron	N/A	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.1874-128T>C		intron	N/A	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.1874-128T>C		intron	N/A	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33919 AN: 152086 Hom.: 4103 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.234 AC: 166617 AN: 710562 Hom.: 21464 AF XY: 0.234 AC XY: 88077 AN XY: 376624

African (AFR) AF: 0.163 AC: 2965 AN: 18244

American (AMR) AF: 0.118 AC: 4253 AN: 36144

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 5027 AN: 20948

East Asian (EAS) AF: 0.502 AC: 16566 AN: 32986

South Asian (SAS) AF: 0.175 AC: 11591 AN: 66336

European-Finnish (FIN) AF: 0.233 AC: 10125 AN: 43400

Middle Eastern (MID) AF: 0.203 AC: 771 AN: 3790

European-Non Finnish (NFE) AF: 0.237 AC: 107222 AN: 453142

Other (OTH) AF: 0.228 AC: 8097 AN: 35572

GnomAD4 genome AF: 0.223 AC: 33914 AN: 152204 Hom.: 4100 Cov.: 32 AF XY: 0.221 AC XY: 16425 AN XY: 74412

African (AFR) AF: 0.171 AC: 7109 AN: 41530

American (AMR) AF: 0.170 AC: 2598 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 893 AN: 3468

East Asian (EAS) AF: 0.462 AC: 2393 AN: 5178

South Asian (SAS) AF: 0.184 AC: 888 AN: 4828

European-Finnish (FIN) AF: 0.244 AC: 2581 AN: 10582

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16691 AN: 67994

Other (OTH) AF: 0.213 AC: 450 AN: 2116

Alfa AF: 0.216 Hom.: 494

Bravo AF: 0.214

Asia WGS AF: 0.295 AC: 1025 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.41
DANN	Benign	0.44
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs7597768; hg19: chr2-191841879;