3-57097694-G-A

Position:

chr3-57097694-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017563.5(IL17RD):c.2009C>T(p.Pro670Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000844 in 1,605,802 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 2 hom. )

Consequence

IL17RD
NM_017563.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.52

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:

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=0.10057995).

BS2

High AC in GnomAd4 at 93 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RD	NM_017563.5 linkuse as main transcript	c.2009C>T	p.Pro670Leu	missense_variant	12/13	ENST00000296318.12	NP_060033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RD	ENST00000296318.12 linkuse as main transcript	c.2009C>T	p.Pro670Leu	missense_variant	12/13	1	NM_017563.5	ENSP00000296318	P1	Q8NFM7-1
IL17RD	ENST00000320057.9 linkuse as main transcript	c.1577C>T	p.Pro526Leu	missense_variant	13/14	1		ENSP00000322250		Q8NFM7-2
IL17RD	ENST00000463523.5 linkuse as main transcript	c.1577C>T	p.Pro526Leu	missense_variant	12/13	1		ENSP00000417516		Q8NFM7-2
IL17RD	ENST00000469841.5 linkuse as main transcript	n.1946C>T		non_coding_transcript_exon_variant	12/12	2

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000581

AC:

138

AN:

237340

Hom.:

AF XY:

0.000569

AC XY:

AN XY:

128322

show subpopulations

Gnomad AFR exome

AF:

0.000205

Gnomad AMR exome

AF:

0.0000906

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000846

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000434

Gnomad NFE exome

AF:

0.000933

Gnomad OTH exome

AF:

0.00138

GnomAD4 exome

AF:

0.000868

AC:

1262

AN:

1453492

Hom.:

Cov.:

AF XY:

0.000838

AC XY:

605

AN XY:

722160

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000688

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000355

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.000417

GnomAD4 genome

AF:

0.000611

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000931

Hom.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.000569

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous state in an individual in published literature, however they were clinically unaffected (PMID: 23643382); This variant is associated with the following publications: (PMID: 23643382) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 06, 2023	This variant is present in population databases (rs143119752, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 670 of the IL17RD protein (p.Pro670Leu). This variant has not been reported in the literature in individuals affected with IL17RD-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL17RD protein function. ClinVar contains an entry for this variant (Variation ID: 1442770). -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.2009C>T (p.P670L) alteration is located in exon 12 (coding exon 12) of the IL17RD gene. This alteration results from a C to T substitution at nucleotide position 2009, causing the proline (P) at amino acid position 670 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;.;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.2

N;N;N;.

REVEL

Benign

0.19

Sift

Uncertain

0.0060

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.62

MVP

0.45

MPC

0.52

ClinPred

0.070

GERP RS

5.8

Varity_R

0.15

gMVP

0.45

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