22-49997383-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001371417.1(IL17REL):c.1194G>A(p.Arg398=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IL17REL NM_001371417.1 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.88

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03744763).
• BP7: Synonymous conserved (PhyloP=-3.88 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17REL	NM_001371417.1	c.1194G>A	p.Arg398=	synonymous_variant	13/15	ENST00000695950.1
IL17REL	NM_001371416.1	c.1127G>A	p.Gly376Glu	missense_variant	13/15
IL17REL	NM_001001694.3	c.911G>A	p.Gly304Glu	missense_variant	13/15
IL17REL	XR_001755245.2	n.1313G>A		non_coding_transcript_exon_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17REL	ENST00000695950.1	c.1194G>A	p.Arg398=	synonymous_variant	13/15		NM_001371417.1	A2
IL17REL	ENST00000695951.1	c.1127G>A	p.Gly376Glu	missense_variant	13/15			P2
IL17REL	ENST00000389983.7	c.*1046G>A		3_prime_UTR_variant, NMD_transcript_variant	13/15	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461546 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727086

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 21, 2023

The c.911G>A (p.G304E) alteration is located in exon 13 (coding exon 10) of the IL17REL gene. This alteration results from a G to A substitution at nucleotide position 911, causing the glycine (G) at amino acid position 304 to be replaced by a glutamic acid (E). 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	0.073
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.44
Dann	Benign	0.54
DEOGEN2	Benign	0.00045	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.31	T;.
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.0040
Sift	Uncertain	0.013	D;D
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.093
MutPred		0.15		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.040
MPC		0.28
ClinPred		0.089	T
GERP RS		-2.9
Varity_R		0.041
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1044083555; hg19: chr22-50435812;