1-154405680-A-G

Position:

• chr1-154405680-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000565.4(IL6R):​c.51A>G​(p.Gly17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,528,286 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (22 hom.)
• Consequence: IL6R NM_000565.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.722

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-154405680-A-G is Benign according to our data. Variant chr1-154405680-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1164781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.722 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL6R	NM_000565.4	c.51A>G	p.Gly17=	synonymous_variant	1/10	ENST00000368485.8	NP_000556.1
IL6R-AS1	NR_147855.1	n.126+759T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.51A>G	p.Gly17=	synonymous_variant	1/10	1	NM_000565.4	ENSP00000357470	P1
IL6R-AS1	ENST00000424435.1	n.126+759T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152036 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00348 AC: 430 AN: 123670 Hom.: 1 AF XY: 0.00321 AC XY: 219 AN XY: 68204

Gnomad AFR exome AF: 0.000403

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.000103

Gnomad SAS exome AF: 0.0000908

Gnomad FIN exome AF: 0.000563

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00471

GnomAD4 exome AF: 0.00396 AC: 5449 AN: 1376136 Hom.: 22 Cov.: 32 AF XY: 0.00383 AC XY: 2603 AN XY: 679126

Gnomad4 AFR exome AF: 0.000493

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.0000859

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.000447

Gnomad4 NFE exome AF: 0.00414

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152150 Hom.: 1 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74384

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00346

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00535 Hom.: 1

Bravo AF: 0.00306

Asia WGS AF: 0.000578 AC: 3 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	IL6R: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

IL6R-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.4
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs528464156; hg19: chr1-154378156;