chr3-57106004-C-T

Variant names:

• chr3-57106004-C-T
• rs727505366
• NM_017563.5:c.600G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_017563.5(IL17RD):​c.600G>A​(p.Trp200*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL17RD NM_017563.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.54
• Publications: 1 publications found

Genes affected

IL17RD (HGNC:17616): (interleukin 17 receptor D) This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. The encoded protein is a component of the interleukin-17 receptor signaling complex, and the interaction between this protein and IL-17R does not require the interleukin. The gene product also affects fibroblast growth factor signaling, inhibiting or stimulating growth through MAPK/ERK signaling. Alternate splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

IL17RD Gene-Disease associations (from GenCC):

• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 18 with or without anosmia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-57106004-C-T is Pathogenic according to our data. Variant chr3-57106004-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 180146.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017563.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL17RD	NM_017563.5	MANE Select	c.600G>A	p.Trp200*	stop_gained	Exon 7 of 13	NP_060033.3
	IL17RD	NM_001318864.2		c.168G>A	p.Trp56*	stop_gained	Exon 8 of 14	NP_001305793.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL17RD	ENST00000296318.12	TSL:1 MANE Select	c.600G>A	p.Trp200*	stop_gained	Exon 7 of 13	ENSP00000296318.7
	IL17RD	ENST00000320057.9	TSL:1	c.168G>A	p.Trp56*	stop_gained	Exon 8 of 14	ENSP00000322250.5
	IL17RD	ENST00000463523.5	TSL:1	c.168G>A	p.Trp56*	stop_gained	Exon 7 of 13	ENSP00000417516.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461542 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727024

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Delayed puberty Pathogenic:1

Nov 01, 2014

Chan Lab, Boston Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.5
Vest4		0.89
GERP RS		5.8
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs727505366; hg19: chr3-57140032;