Genetic Variant IL17RD:p.Ser683* (chr3-57097655-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017563.5(IL17RD):c.2048C>A(p.Ser683*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IL17RD
NM_017563.5 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.55

Publications

0 publications found

Variant links:

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)

IL17RD links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL17RD	NM_017563.5	MANE Select	c.2048C>A	p.Ser683*	stop_gained	Exon 12 of 13	NP_060033.3	Q8NFM7-1
	IL17RD	NM_001318864.2		c.1616C>A	p.Ser539*	stop_gained	Exon 13 of 14	NP_001305793.1	Q8NFM7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL17RD	ENST00000296318.12	TSL:1 MANE Select	c.2048C>A	p.Ser683*	stop_gained	Exon 12 of 13	ENSP00000296318.7	Q8NFM7-1
IL17RD	ENST00000320057.9	TSL:1	c.1616C>A	p.Ser539*	stop_gained	Exon 13 of 14	ENSP00000322250.5	Q8NFM7-2
IL17RD	ENST00000463523.5	TSL:1	c.1616C>A	p.Ser539*	stop_gained	Exon 12 of 13	ENSP00000417516.1	Q8NFM7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449224

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719494

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33262

American (AMR)

AF:

0.00

AC:

AN:

42720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25730

East Asian (EAS)

AF:

0.00

AC:

AN:

39226

South Asian (SAS)

AF:

0.00

AC:

AN:

83648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106462

Other (OTH)

AF:

0.00

AC:

AN:

59954

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

PhyloP100

2.5

Vest4

0.91

GERP RS

2.7

Mutation Taster

=28/172

disease causing (fs/PTC)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over