2-190986920-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007315.4(STAT1):c.1155G>A(p.Thr385=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,614,156 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (27 hom.)
• Consequence: STAT1 NM_007315.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.709

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-190986920-C-T is Benign according to our data. Variant chr2-190986920-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 333279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190986920-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.709 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00286 (436/152278) while in subpopulation SAS AF= 0.00518 (25/4826). AF 95% confidence interval is 0.0036. There are 1 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT1	NM_007315.4	c.1155G>A	p.Thr385=	synonymous_variant	14/25	ENST00000361099.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT1	ENST00000361099.8	c.1155G>A	p.Thr385=	synonymous_variant	14/25	1	NM_007315.4	P4

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00416 AC: 1046 AN: 251400 Hom.: 9 AF XY: 0.00446 AC XY: 606 AN XY: 135862

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00627

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00377 AC: 5507 AN: 1461878 Hom.: 27 Cov.: 32 AF XY: 0.00382 AC XY: 2779 AN XY: 727242

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00636

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.00323

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74462

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00415 Hom.: 0

Bravo AF: 0.00259

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00391

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 10, 2021

- -

Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

STAT1: BP4, BP7, BS2 -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.63
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs41270237; hg19: chr2-191851646;