Genetic Variant NM_000565.4:c.1073A>T (chr1-154454494-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000565.4(IL6R):c.1073A>T(p.Asp358Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D358A) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Consequence

IL6R
NM_000565.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.519

Publications

611 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

IL6R links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL6R	NM_000565.4	MANE Select	c.1073A>T	p.Asp358Val	missense	Exon 9 of 10	NP_000556.1
IL6R	NM_001382769.1		c.1172A>T	p.Asp391Val	missense	Exon 10 of 11	NP_001369698.1
IL6R	NM_001382770.1		c.1166A>T	p.Asp389Val	missense	Exon 10 of 11	NP_001369699.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL6R	ENST00000368485.8	TSL:1 MANE Select	c.1073A>T	p.Asp358Val	missense	Exon 9 of 10	ENSP00000357470.3
IL6R	ENST00000344086.8	TSL:1	c.1066+4514A>T		intron	N/A	ENSP00000340589.4
IL6R	ENST00000858510.1		c.1265A>T	p.Asp422Val	missense	Exon 11 of 12	ENSP00000528569.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.31

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.66

M_CAP

Benign

0.0051

MetaRNN

Benign

0.092

MetaSVM

Benign

-0.89

PhyloP100

0.52

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.14

Sift

Benign

0.20

Sift4G

Benign

0.19

Polyphen

0.046

Vest4

0.22

MutPred

0.32

Loss of sheet (P = 0.0104)

MVP

0.46

MPC

0.43

ClinPred

0.74

GERP RS

2.9

Varity_R

0.25

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: -6

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over