1-154405684-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000565.4(IL6R):c.55G>A(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000858 in 1,526,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: IL6R NM_000565.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.271

Genes affected

IL6R (HGNC:6019): (interleukin 6 receptor) This gene encodes a subunit of the interleukin 6 (IL6) receptor complex. Interleukin 6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been identified in this gene. A pseudogene of this gene is found on chromosome 9. [provided by RefSeq, Aug 2020]

IL6R-AS1 (HGNC:53716): (IL6R antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16743588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6R	NM_000565.4	c.55G>A	p.Ala19Thr	missense_variant	1/10	ENST00000368485.8
IL6R-AS1	NR_147855.1	n.126+755C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6R	ENST00000368485.8	c.55G>A	p.Ala19Thr	missense_variant	1/10	1	NM_000565.4	P1
IL6R-AS1	ENST00000424435.1	n.126+755C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000114 AC: 14 AN: 122364 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000168

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: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000822 AC: 113 AN: 1374660 Hom.: 0 Cov.: 32 AF XY: 0.0000855 AC XY: 58 AN XY: 678356

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000143

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: 0.0000967

Gnomad4 OTH exome AF: 0.0000698

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.0000132 AC: 1

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

Invitae

Jun 17, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 19 of the IL6R protein (p.Ala19Thr). This variant is present in population databases (rs758469371, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with IL6R-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.25
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.77	T
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.92, 0.99	.;P;D;.
Vest4		0.053
MutPred		0.26		Gain of glycosylation at A19 (P = 0.005);Gain of glycosylation at A19 (P = 0.005);Gain of glycosylation at A19 (P = 0.005);Gain of glycosylation at A19 (P = 0.005);
MVP		0.50
MPC		0.24
ClinPred		0.11	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.047
gMVP		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: rs758469371; hg19: chr1-154378160;