chr5-55941131-T-A

Position:

• chr5-55941131-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002184.4(IL6ST):​c.2708A>T​(p.Lys903Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL6ST NM_002184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6ST	NM_002184.4	c.2708A>T	p.Lys903Ile	missense_variant	17/17	ENST00000381298.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6ST	ENST00000381298.7	c.2708A>T	p.Lys903Ile	missense_variant	17/17	1	NM_002184.4	P1
	ENST00000576302.1	n.267+12T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with IL6ST-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 903 of the IL6ST protein (p.Lys903Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.4	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;D;.;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.57
MutPred		0.30		Loss of ubiquitination at K903 (P = 0.0017);Loss of ubiquitination at K903 (P = 0.0017);Loss of ubiquitination at K903 (P = 0.0017);.;
MVP		0.70
MPC		0.78
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.44
gMVP		0.60

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: rs879036952; hg19: chr5-55236959;