rs6894414

Variant names:

• chr5-55956667-A-G
• rs6894414
• NM_002184.4:c.1057-432T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002184.4(IL6ST):​c.1057-432T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,136 control chromosomes in the GnomAD database, including 1,217 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1217 hom., cov: 32)
• Consequence: IL6ST NM_002184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6ST	NM_002184.4	c.1057-432T>C		intron_variant	Intron 9 of 16	ENST00000381298.7	NP_002175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6ST	ENST00000381298.7	c.1057-432T>C		intron_variant	Intron 9 of 16	1	NM_002184.4	ENSP00000370698.2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18599 AN: 152018 Hom.: 1213 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.125

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.122 AC: 18627 AN: 152136 Hom.: 1217 Cov.: 32 AF XY: 0.119 AC XY: 8869 AN XY: 74380

African (AFR) AF: 0.145 AC: 6025 AN: 41500

American (AMR) AF: 0.102 AC: 1564 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3472

East Asian (EAS) AF: 0.0329 AC: 171 AN: 5190

South Asian (SAS) AF: 0.0699 AC: 337 AN: 4824

European-Finnish (FIN) AF: 0.132 AC: 1396 AN: 10546

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8163 AN: 67994

Other (OTH) AF: 0.124 AC: 261 AN: 2110

Alfa AF: 0.121 Hom.: 400

Bravo AF: 0.124

Asia WGS AF: 0.0820 AC: 286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.5
DANN	Benign	0.69
PhyloP100		0.064
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: rs6894414; hg19: chr5-55252495;