chr3-57110230-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017563.5(IL17RD):c.392A>C(p.Lys131Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00115 in 1,607,560 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 7 hom. )

Consequence

IL17RD
NM_017563.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:1

Conservation

PhyloP100: 5.73

Publications

13 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:

ENSG00000297895 (HGNC:):

ENSG00000297895 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07136911).

BS2

High AC in GnomAd4 at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL17RD	NM_017563.5 link	c.392A>C	p.Lys131Thr	missense_variant	Exon 4 of 13	ENST00000296318.12	NP_060033.3	Q8NFM7-1B4DXM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL17RD	ENST00000296318.12 link	c.392A>C	p.Lys131Thr	missense_variant	Exon 4 of 13	1	NM_017563.5	ENSP00000296318.7		Q8NFM7-1

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000893

AC:

214

AN:

239576

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.000268

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000521

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.00119

AC:

1735

AN:

1455194

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

913

AN XY:

723010

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33408

American (AMR)

AF:

0.000227

AC:

AN:

44014

Ashkenazi Jewish (ASJ)

AF:

0.0000772

AC:

AN:

25910

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00278

AC:

235

AN:

84440

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00123

AC:

1361

AN:

1108790

Other (OTH)

AF:

0.00133

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

168

252

336

420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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

AF:

0.000702

AC:

107

AN:

152366

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41592

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000834

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000723

AC:

ExAC

AF:

0.000935

AC:

113

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Apr 05, 2018

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: IL17RD c.392A>C (p.Lys131Thr) results in a non-conservative amino acid change located in the Interleukin 17 receptor D, N-terminal (IPR031951) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 1607560 control chromosomes in the gnomAD database (v4.0.0), including 8 homozygotes. This frequency does not allow conclusion about variant significance. c.392A>C has been reported in the literature in individuals affected with Kallman syndrome (Miraoui_2013). These reports do not provide unequivocal conclusions about association of the variant with Hypogonadotropic Hypogonadism 18 With Or Without Anosmia. At least one publication reports experimental evidence evaluating an impact on protein function indicating it alters protein function (Miraoui_2013). The following publication have been ascertained in the context of this evaluation (PMID: 23643382). ClinVar contains an entry for this variant (Variation ID: 50867). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1Benign:1

Apr 24, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in the heterozygous state in two individuals with Kallman syndrome and an individual with self-limited delayed puberty, as well as in one control sample, in the published literature (Miraoui et al., 2013; Zhu et al., 2015); Published functional studies show that the K131T variant disrupts normal protein function (Miraoui et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23643382, 25636053, 34426522) -

Dec 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Hypogonadotropic hypogonadism 18 with anosmia

Pathogenic:1

May 02, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.024

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

5.7

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

REVEL

Benign

0.23

Sift

Benign

0.12

Sift4G

Uncertain

0.0060

Polyphen

0.99

Vest4

0.89

MVP

0.48

MPC

0.30

ClinPred

0.042

GERP RS

5.7

Varity_R

0.19

gMVP

0.61

Mutation Taster

=9/91

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over