3-57097694-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

7
3
9

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]

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 UniProt
IL17RDNM_017563.5 linkuse as main transcriptc.2009C>T p.Pro670Leu missense_variant 12/13 ENST00000296318.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IL17RDENST00000296318.12 linkuse as main transcriptc.2009C>T p.Pro670Leu missense_variant 12/131 NM_017563.5 P1Q8NFM7-1
IL17RDENST00000320057.9 linkuse as main transcriptc.1577C>T p.Pro526Leu missense_variant 13/141 Q8NFM7-2
IL17RDENST00000463523.5 linkuse as main transcriptc.1577C>T p.Pro526Leu missense_variant 12/131 Q8NFM7-2
IL17RDENST00000469841.5 linkuse as main transcriptn.1946C>T non_coding_transcript_exon_variant 12/122

Frequencies

GnomAD3 genomes
AF:
0.000611
AC:
93
AN:
152192
Hom.:
0
Cov.:
32
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.:
0
AF XY:
0.000569
AC XY:
73
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.:
2
Cov.:
32
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:
93
AN:
152310
Hom.:
0
Cov.:
32
AF XY:
0.000551
AC XY:
41
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.:
0
Bravo
AF:
0.000563
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00198
AC:
17
ExAC
AF:
0.000569
AC:
69

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 submitterclinical testingGeneDxJun 12, 2023In 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 06, 2023This 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 submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 18, 2023The 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
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.23
T;.;.;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;.;.;D
M_CAP
Uncertain
0.089
D
MetaRNN
Benign
0.10
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.81
D
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
T
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.

Other links and lift over

dbSNP: rs143119752; hg19: chr3-57131722; API