1-154434943-A-C

Variant names:

• chr1-154434943-A-C
• rs7518199
• NM_000565.4:c.641-47A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000565.4(IL6R):​c.641-47A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,597,692 control chromosomes in the GnomAD database, including 128,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10131 hom., cov: 30)
  • Exomes 𝑓: 0.40 (118546 hom.)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0310
• Publications: 49 publications found

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 Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 5, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-154434943-A-C is Benign according to our data. Variant chr1-154434943-A-C is described in ClinVar as Benign. ClinVar VariationId is 2688545.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000565.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	NM_000565.4	MANE Select	c.641-47A>C		intron	N/A	NP_000556.1	P08887-1
	IL6R	NM_001382769.1		c.641-47A>C		intron	N/A	NP_001369698.1
	IL6R	NM_001382770.1		c.641-47A>C		intron	N/A	NP_001369699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.641-47A>C		intron	N/A	ENSP00000357470.3	P08887-1
	IL6R	ENST00000344086.8	TSL:1	c.641-47A>C		intron	N/A	ENSP00000340589.4	P08887-2
	IL6R	ENST00000622330.5	TSL:1	c.641-47A>C		intron	N/A	ENSP00000477739.1	A0A087WTB5

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53348 AN: 151652 Hom.: 10128 Cov.: 30

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.375

GnomAD2 exomes AF: 0.394 AC: 94493 AN: 240104 AF XY: 0.388

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.562

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.394

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.401 AC: 579609 AN: 1445920 Hom.: 118546 Cov.: 29 AF XY: 0.398 AC XY: 285960 AN XY: 719104

African (AFR) AF: 0.216 AC: 7159 AN: 33162

American (AMR) AF: 0.556 AC: 24476 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 9987 AN: 25558

East Asian (EAS) AF: 0.401 AC: 15815 AN: 39452

South Asian (SAS) AF: 0.315 AC: 26843 AN: 85170

European-Finnish (FIN) AF: 0.302 AC: 15939 AN: 52794

Middle Eastern (MID) AF: 0.365 AC: 1636 AN: 4478

European-Non Finnish (NFE) AF: 0.413 AC: 454932 AN: 1101542

Other (OTH) AF: 0.382 AC: 22822 AN: 59712

GnomAD4 genome AF: 0.352 AC: 53370 AN: 151772 Hom.: 10131 Cov.: 30 AF XY: 0.347 AC XY: 25714 AN XY: 74166

African (AFR) AF: 0.224 AC: 9282 AN: 41356

American (AMR) AF: 0.508 AC: 7742 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1336 AN: 3468

East Asian (EAS) AF: 0.374 AC: 1921 AN: 5138

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4812

European-Finnish (FIN) AF: 0.286 AC: 3018 AN: 10540

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27274 AN: 67908

Other (OTH) AF: 0.371 AC: 781 AN: 2104

Alfa AF: 0.391 Hom.: 32202

Bravo AF: 0.369

Asia WGS AF: 0.301 AC: 1047 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.3
DANN	Benign	0.45
PhyloP100		-0.031
PromoterAI		-0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs7518199; hg19: chr1-154407419; COSMIC: COSV107420263; COSMIC: COSV107420263;