rs1373998

Positions:

• chr5-55959737-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002184.4(IL6ST):​c.973+665C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 751,860 control chromosomes in the GnomAD database, including 13,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (6916 hom., cov: 32)
  • Exomes 𝑓: 0.13 (6841 hom.)
• Consequence: IL6ST NM_002184.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.381

Genes affected

IL6ST (HGNC:6021): (interleukin 6 cytokine family signal transducer) The protein encoded by this gene is a signal transducer shared by many cytokines, including interleukin 6 (IL6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM). This protein functions as a part of the cytokine receptor complex. The activation of this protein is dependent upon the binding of cytokines to their receptors. vIL6, a protein related to IL6 and encoded by the Kaposi sarcoma-associated herpesvirus, can bypass the interleukin 6 receptor (IL6R) and directly activate this protein. Knockout studies in mice suggest that this gene plays a critical role in regulating myocyte apoptosis. Alternatively spliced transcript variants have been described. A related pseudogene has been identified on chromosome 17. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-55959737-G-A is Benign according to our data. Variant chr5-55959737-G-A is described in ClinVar as [Benign]. Clinvar id is 2688475.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6ST	NM_002184.4	c.973+665C>T		intron_variant		ENST00000381298.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6ST	ENST00000381298.7	c.973+665C>T		intron_variant		1	NM_002184.4	P1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36548 AN: 151984 Hom.: 6894 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.0761

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.132 AC: 79253 AN: 599758 Hom.: 6841 AF XY: 0.128 AC XY: 40219 AN XY: 313122

Gnomad4 AFR exome AF: 0.539

Gnomad4 AMR exome AF: 0.0965

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.0310

Gnomad4 SAS exome AF: 0.0802

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.241 AC: 36625 AN: 152102 Hom.: 6916 Cov.: 32 AF XY: 0.233 AC XY: 17360 AN XY: 74362

Gnomad4 AFR AF: 0.527

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.0332

Gnomad4 SAS AF: 0.0751

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.218

Alfa AF: 0.201 Hom.: 756

Bravo AF: 0.257

Asia WGS AF: 0.105 AC: 366 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.57
DANN	Benign	0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs1373998; hg19: chr5-55255565;