chr2-191058115-G-A

Position:

• chr2-191058115-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003151.4(STAT4):​c.1113-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,613,274 control chromosomes in the GnomAD database, including 406,290 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (28572 hom., cov: 31)
  • Exomes 𝑓: 0.71 (377718 hom.)
• Consequence: STAT4 NM_003151.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0006460
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0620

Genes affected

STAT4 (HGNC:11365): (signal transducer and activator of transcription 4) The protein encoded by this gene is a member of the STAT family of transcription factors. 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. This protein is essential for mediating responses to IL12 in lymphocytes, and regulating the differentiation of T helper cells. Mutations in this gene may be associated with systemic lupus erythematosus and rheumatoid arthritis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Aug 2011]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-191058115-G-A is Benign according to our data. Variant chr2-191058115-G-A is described in ClinVar as [Benign]. Clinvar id is 403495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT4	NM_003151.4	c.1113-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000392320.7	NP_003142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT4	ENST00000392320.7	c.1113-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003151.4	ENSP00000376134	P1
STAT4	ENST00000358470.8	c.1113-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000351255	P1
	ENST00000658263.1	n.1301-6669G>A		intron_variant, non_coding_transcript_variant
STAT4	ENST00000495849.5	n.1181-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86371 AN: 151806 Hom.: 28577 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.602

GnomAD3 exomes AF: 0.642 AC: 160976 AN: 250916 Hom.: 54340 AF XY: 0.657 AC XY: 89063 AN XY: 135610

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.512

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.517

Gnomad SAS exome AF: 0.662

Gnomad FIN exome AF: 0.692

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.712 AC: 1040434 AN: 1461350 Hom.: 377718 Cov.: 42 AF XY: 0.712 AC XY: 517871 AN XY: 727016

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.669

Gnomad4 EAS exome AF: 0.556

Gnomad4 SAS exome AF: 0.659

Gnomad4 FIN exome AF: 0.694

Gnomad4 NFE exome AF: 0.749

Gnomad4 OTH exome AF: 0.677

GnomAD4 genome AF: 0.569 AC: 86369 AN: 151924 Hom.: 28572 Cov.: 31 AF XY: 0.568 AC XY: 42203 AN XY: 74244

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.553

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.530

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.700

Gnomad4 NFE AF: 0.749

Gnomad4 OTH AF: 0.600

Alfa AF: 0.688 Hom.: 48606

Bravo AF: 0.540

Asia WGS AF: 0.559 AC: 1945 AN: 3478

EpiCase AF: 0.740

EpiControl AF: 0.737

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.7
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00065
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.030		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: rs3024866; hg19: chr2-191922841; COSMIC: COSV61831638;