chr3-57110230-T-G

Position:

chr3-57110230-T-G

Variant summary

Our verdict is Likely benign. Variant got -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

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 links:

IL17RD (HGNC:):

IL17RD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 107 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RD	NM_017563.5 linkuse as main transcript	c.392A>C	p.Lys131Thr	missense_variant	4/13	ENST00000296318.12	NP_060033.3	Q8NFM7-1B4DXM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RD	ENST00000296318.12 linkuse as main transcript	c.392A>C	p.Lys131Thr	missense_variant	4/13	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

GnomAD3 exomes

AF:

0.000893

AC:

214

AN:

239576

Hom.:

AF XY:

0.00105

AC XY:

136

AN XY:

129460

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 SAS exome

AF:

0.00244

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

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.0000772

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00278

Gnomad4 FIN exome

AF:

0.000659

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.00133

GnomAD4 genome

AF:

0.000702

AC:

107

AN:

152366

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000845

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

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2018	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2023	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) -

Delayed puberty

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

Hypogonadotropic hypogonadism 18 with anosmia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over