2-191008827-A-T

Variant names:

• chr2-191008827-A-T
• rs10199181
• NM_007315.4:c.273+136T>A

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.273+136T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 895,406 control chromosomes in the GnomAD database, including 77,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.44 (15850 hom., cov: 33)
  • Exomes 𝑓: 0.40 (61831 hom.)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.127
• Publications: 21 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, Orphanet
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-191008827-A-T is Benign according to our data. Variant chr2-191008827-A-T is described in ClinVar as Benign. ClinVar VariationId is 1258219.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.273+136T>A		intron_variant	Intron 4 of 24	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.273+136T>A		intron_variant	Intron 4 of 24	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67432 AN: 151986 Hom.: 15824 Cov.: 33

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.442

GnomAD4 exome AF: 0.399 AC: 296427 AN: 743302 Hom.: 61831 AF XY: 0.399 AC XY: 153209 AN XY: 384116

African (AFR) AF: 0.576 AC: 9949 AN: 17272

American (AMR) AF: 0.440 AC: 9523 AN: 21666

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 8349 AN: 17992

East Asian (EAS) AF: 0.709 AC: 22983 AN: 32426

South Asian (SAS) AF: 0.359 AC: 20157 AN: 56148

European-Finnish (FIN) AF: 0.331 AC: 10895 AN: 32924

Middle Eastern (MID) AF: 0.483 AC: 1509 AN: 3126

European-Non Finnish (NFE) AF: 0.376 AC: 197684 AN: 525914

Other (OTH) AF: 0.429 AC: 15378 AN: 35834

GnomAD4 genome AF: 0.444 AC: 67498 AN: 152104 Hom.: 15850 Cov.: 33 AF XY: 0.440 AC XY: 32722 AN XY: 74348

African (AFR) AF: 0.565 AC: 23445 AN: 41464

American (AMR) AF: 0.440 AC: 6725 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1622 AN: 3468

East Asian (EAS) AF: 0.720 AC: 3731 AN: 5180

South Asian (SAS) AF: 0.354 AC: 1707 AN: 4822

European-Finnish (FIN) AF: 0.332 AC: 3510 AN: 10566

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.374 AC: 25400 AN: 67994

Other (OTH) AF: 0.447 AC: 946 AN: 2114

Alfa AF: 0.385 Hom.: 1422

Bravo AF: 0.463

Asia WGS AF: 0.549 AC: 1914 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.32
PhyloP100		-0.13
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: rs10199181; hg19: chr2-191873553;