Genetic Variant IL17REL:c.1258-1G>A (chr22-49997075-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001371417.1(IL17REL):c.1258-1G>A variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IL17REL
NM_001371417.1 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Variant links:

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]

IL17REL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.053149607 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.4, offset of 1, new splice context is: cctgccctcccccacccaAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
IL17REL	NM_001371417.1 link	c.1258-1G>A	splice_acceptor_variant, intron_variant	Intron 13 of 14	ENST00000695950.1	NP_001358346.1
IL17REL	NM_001371416.1 link	c.1191-1G>A	splice_acceptor_variant, intron_variant	Intron 13 of 14		NP_001358345.1
IL17REL	NM_001001694.3 link	c.975-1G>A	splice_acceptor_variant, intron_variant	Intron 13 of 14		NP_001001694.2	Q6ZVW7
IL17REL	XR_001755245.2 link	n.1377-1G>A	splice_acceptor_variant, intron_variant	Intron 13 of 15

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL17REL	ENST00000695950.1 link	c.1258-1G>A	splice_acceptor_variant, intron_variant	Intron 13 of 14		NM_001371417.1	ENSP00000512282.1	A0A8Q3WKV1
IL17REL	ENST00000695951.1 link	c.1191-1G>A	splice_acceptor_variant, intron_variant	Intron 13 of 14			ENSP00000512283.1	A0A8Q3WLX3
IL17REL	ENST00000389983.7 link	n.*1110-1G>A	splice_acceptor_variant, intron_variant	Intron 13 of 14	2		ENSP00000374633.3	Q6ZVW7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703038

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IL17REL: PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.96

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.058

FATHMM_MKL

Benign

0.094

GERP RS

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.62

Position offset: -2

DS_AL_spliceai

0.76

Position offset: -1

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over