NM_000565.4:c.1073_1074delATinsCG

Variant names:

• chr1-154454494-AT-CG
• NM_000565.4:c.1073_1074delATinsCG
• IL6R p.Asp358Ala

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000565.4(IL6R):c.1073_1074delATinsCG (p.Asp358Ala) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D358A: Benign/Likely_benign (ClinVar VariationId 14660, 2 stars); p.D358V: unknown significance (ClinVar VariationId 4523836); p.D358Y: Uncertain_significance (ClinVar VariationId 1362683, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: IL6R NM_000565.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.519
• Publications: 0 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: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL6R NM_000565.4	MANE Select	c.1073_1074delATinsCG p.Asp358Ala	missense	N/A	Prot: NP_000556.1 UniProt:
	IL6R NM_001382769.1		c.1172_1173delATinsCG p.Asp391Ala	missense	N/A	Prot: NP_001369698.1
	IL6R NM_001382770.1		c.1166_1167delATinsCG p.Asp389Ala	missense	N/A	Prot: NP_001369699.1

IL6R NM_000565.4

MANE Select

HGVSc / HGVSpc.1073_1074delATinsCGp.Asp358Ala

Exon rankN/A

missense

Prot: NP_000556.1UniProt: A0N0L5P08887-1

IL6R NM_001382769.1

HGVSc / HGVSpc.1172_1173delATinsCGp.Asp391Ala

Exon rankN/A

missense

Prot: NP_001369698.1

IL6R NM_001382770.1

HGVSc / HGVSpc.1166_1167delATinsCGp.Asp389Ala

Exon rankN/A

missense

Prot: NP_001369699.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL6R ENST00000368485.8	TSL:1MANE Select	c.1073_1074delATinsCG p.Asp358Ala	missense	N/A	Prot: ENSP00000357470.3 UniProt:
	IL6R ENST00000344086.8	TSL:1	c.1066+4514_1066+4515delATinsCG	intron	Intron 8 of 8	Prot: ENSP00000340589.4 UniProt:
	IL6R ENST00000858510.1		c.1265_1266delATinsCG p.Asp422Ala	missense	N/A	Prot: ENSP00000528569.1 UniProt:

IL6R ENST00000368485.8

TSL:1MANE Select

HGVSc / HGVSpc.1073_1074delATinsCGp.Asp358Ala

Exon rankN/A

missense

Prot: ENSP00000357470.3UniProt: P08887-1

IL6R ENST00000344086.8

TSL:1

HGVSc / HGVSpc.1066+4514_1066+4515delATinsCG

Exon rankIntron 8 of 8

intron

Prot: ENSP00000340589.4UniProt: P08887-2

IL6R ENST00000858510.1

HGVSc / HGVSpc.1265_1266delATinsCGp.Asp422Ala

Exon rankN/A

missense

Prot: ENSP00000528569.1UniProt: A0ACI8RD36

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:30

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.52

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr1-154426970;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar