rs748486078

chr6-52237139-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_052872.4(IL17F):c.284C>T(p.Ser95Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: IL17F NM_052872.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 0.699

Genes affected

IL17F (HGNC:16404): (interleukin 17F) The protein encoded by this gene is a cytokine that shares sequence similarity with IL17. This cytokine is expressed by activated T cells, and has been shown to stimulate the production of several other cytokines, including IL6, IL8, and CSF2/GM_CSF. This cytokine is also found to inhibit the angiogenesis of endothelial cells and induce endothelial cells to produce IL2, TGFB1/TGFB, and monocyte chemoattractant protein-1. [provided by RefSeq, Jul 2008]

LOC124901328 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17F	NM_052872.4	c.284C>T	p.Ser95Leu	missense_variant	3/3	ENST00000336123.5
LOC124901328	XR_007059607.1	n.54G>A		non_coding_transcript_exon_variant	1/3
IL17F	XM_011514276.1	c.284C>T	p.Ser95Leu	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17F	ENST00000336123.5	c.284C>T	p.Ser95Leu	missense_variant	3/3	1	NM_052872.4	P1
IL17F	ENST00000478427.1	n.468C>T		non_coding_transcript_exon_variant	2/2	1
IL17F	ENST00000699946.1	c.284C>T	p.Ser95Leu	missense_variant	4/4			P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000439 AC: 11 AN: 250750 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Candidiasis, familial, 6 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 95 of the IL17F protein (p.Ser95Leu). This variant is present in population databases (rs748486078, gnomAD 0.02%). This missense change has been observed in individual(s) with mucocutaneous candidiasis (PMID: 21350122). This variant is also known as p.Ser65Leu. ClinVar contains an entry for this variant (Variation ID: 30589). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IL17F function (PMID: 21350122, 34587561). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2011	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	0.014
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.79	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.31
Sift	Benign	0.046	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.49		Loss of disorder (P = 0.0735);
MVP		0.64
MPC		0.33
ClinPred		0.70	D
GERP RS		3.7
Varity_R		0.50
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748486078; hg19: chr6-52101937; COSMIC: COSV60233575;