Variant 5-55941107-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002184.4(IL6ST):c.2732G>A(p.Arg911Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R911W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

IL6ST
NM_002184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.80

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24669912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6ST	NM_002184.4 linkuse as main transcript	c.2732G>A	p.Arg911Gln	missense_variant	17/17	ENST00000381298.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6ST	ENST00000381298.7 linkuse as main transcript	c.2732G>A	p.Arg911Gln	missense_variant	17/17	1	NM_002184.4	P1	P40189-1
	ENST00000576302.1 linkuse as main transcript	n.255C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250686

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461208

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 911 of the IL6ST protein (p.Arg911Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IL6ST-related conditions. ClinVar contains an entry for this variant (Variation ID: 1505497). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;T;T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.92

M_CAP

Benign

0.056

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.4

M;M;M;.

MutationTaster

Benign

1.0

D;D;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.2

N;N;.;N

REVEL

Benign

0.12

Sift

Uncertain

0.0070

D;D;.;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.41

MutPred

0.27

Loss of MoRF binding (P = 0.0033);Loss of MoRF binding (P = 0.0033);Loss of MoRF binding (P = 0.0033);.;

MVP

0.58

MPC

0.55

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over