rs1373998

Variant names:

• chr5-55959737-G-A
• rs1373998
• NM_002184.4:c.973+665C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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]

IL6ST Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 4A, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hyper-IgE recurrent infection syndrome 4, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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 rank	MANE	Protein	UniProt
IL6ST	NM_002184.4	c.973+665C>T		intron_variant	Intron 8 of 16	ENST00000381298.7	NP_002175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6ST	ENST00000381298.7	c.973+665C>T		intron_variant	Intron 8 of 16	1	NM_002184.4	ENSP00000370698.2

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

African (AFR) AF: 0.539 AC: 7118 AN: 13214

American (AMR) AF: 0.0965 AC: 2433 AN: 25212

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 1627 AN: 12382

East Asian (EAS) AF: 0.0310 AC: 356 AN: 11502

South Asian (SAS) AF: 0.0802 AC: 5009 AN: 62468

European-Finnish (FIN) AF: 0.134 AC: 1604 AN: 11980

Middle Eastern (MID) AF: 0.162 AC: 352 AN: 2172

European-Non Finnish (NFE) AF: 0.131 AC: 57196 AN: 437142

Other (OTH) AF: 0.150 AC: 3558 AN: 23686

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

African (AFR) AF: 0.527 AC: 21817 AN: 41432

American (AMR) AF: 0.153 AC: 2334 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3468

East Asian (EAS) AF: 0.0332 AC: 172 AN: 5184

South Asian (SAS) AF: 0.0751 AC: 363 AN: 4832

European-Finnish (FIN) AF: 0.140 AC: 1482 AN: 10582

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9250 AN: 67992

Other (OTH) AF: 0.218 AC: 460 AN: 2108

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.38
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: rs1373998; hg19: chr5-55255565;