chr2-190975250-C-T

Variant names:

• chr2-190975250-C-T
• rs1914408
• NM_007315.4:c.2136-318G>A

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.2136-318G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 455,736 control chromosomes in the GnomAD database, including 10,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3508 hom., cov: 32)
  • Exomes 𝑓: 0.21 (7348 hom.)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0310
• Publications: 20 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=-0.8).
• BP6: Variant 2-190975250-C-T is Benign according to our data. Variant chr2-190975250-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 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.2136-318G>A		intron	N/A	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.2172-318G>A		intron	N/A	NP_001371820.1
	STAT1	NM_001384886.1		c.2160-318G>A		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.2136-318G>A		intron	N/A	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.2136-318G>A		intron	N/A	ENSP00000386244.1	P42224-1
	STAT1	ENST00000673952.1		c.2136-318G>A		intron	N/A	ENSP00000501115.1	A0A669KB53

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31647 AN: 151896 Hom.: 3508 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.200

GnomAD4 exome AF: 0.212 AC: 64482 AN: 303722 Hom.: 7348 AF XY: 0.211 AC XY: 35962 AN XY: 170218

African (AFR) AF: 0.166 AC: 1305 AN: 7880

American (AMR) AF: 0.120 AC: 2475 AN: 20540

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 1984 AN: 8736

East Asian (EAS) AF: 0.327 AC: 3538 AN: 10810

South Asian (SAS) AF: 0.173 AC: 9141 AN: 52986

European-Finnish (FIN) AF: 0.144 AC: 3831 AN: 26576

Middle Eastern (MID) AF: 0.208 AC: 559 AN: 2690

European-Non Finnish (NFE) AF: 0.242 AC: 38633 AN: 159348

Other (OTH) AF: 0.213 AC: 3016 AN: 14156

GnomAD4 genome AF: 0.208 AC: 31647 AN: 152014 Hom.: 3508 Cov.: 32 AF XY: 0.202 AC XY: 15049 AN XY: 74330

African (AFR) AF: 0.169 AC: 7002 AN: 41458

American (AMR) AF: 0.167 AC: 2556 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3472

East Asian (EAS) AF: 0.310 AC: 1596 AN: 5154

South Asian (SAS) AF: 0.174 AC: 840 AN: 4816

European-Finnish (FIN) AF: 0.156 AC: 1648 AN: 10576

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16427 AN: 67946

Other (OTH) AF: 0.204 AC: 431 AN: 2110

Alfa AF: 0.209 Hom.: 739

Bravo AF: 0.206

Asia WGS AF: 0.243 AC: 846 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		-0.031
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: rs1914408; hg19: chr2-191839976; COSMIC: COSV63114929; COSMIC: COSV63114929;