22-49997703-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001371417.1(IL17REL):c.1075G>A(p.Glu359Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: IL17REL NM_001371417.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.53

Genes affected

IL17REL (HGNC:33808): (interleukin 17 receptor E like) Predicted to enable interleukin-17 receptor activity. Predicted to be involved in cytokine-mediated signaling pathway. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032895237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17REL	NM_001371417.1	c.1075G>A	p.Glu359Lys	missense_variant	12/15	ENST00000695950.1
IL17REL	NM_001371416.1	c.1075G>A	p.Glu359Lys	missense_variant	12/15
IL17REL	NM_001001694.3	c.859G>A	p.Glu287Lys	missense_variant	12/15
IL17REL	XR_001755245.2	n.1194G>A		non_coding_transcript_exon_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17REL	ENST00000695950.1	c.1075G>A	p.Glu359Lys	missense_variant	12/15		NM_001371417.1	A2
IL17REL	ENST00000695951.1	c.1075G>A	p.Glu359Lys	missense_variant	12/15			P2
IL17REL	ENST00000389983.7	c.*994G>A		3_prime_UTR_variant, NMD_transcript_variant	12/15	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251040 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.859G>A (p.E287K) alteration is located in exon 12 (coding exon 9) of the IL17REL gene. This alteration results from a G to A substitution at nucleotide position 859, causing the glutamic acid (E) at amino acid position 287 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.47
Dann	Benign	0.46
DEOGEN2	Benign	0.0014	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.47	T;.
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.0010
Sift	Benign	0.58	T;T
Sift4G	Benign	0.87	T;T
Polyphen		0.0030	B;B
Vest4		0.11
MutPred		0.33		Gain of methylation at E287 (P = 0.0017);Gain of methylation at E287 (P = 0.0017);
MVP		0.014
MPC		0.25
ClinPred		0.019	T
GERP RS		-3.5
Varity_R		0.027
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1394467999; hg19: chr22-50436132; COSMIC: COSV58007691;