1-173757077-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The ENST00000209884.5(KLHL20):​c.1069G>A​(p.Gly357Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

KLHL20
ENST00000209884.5 missense

Scores

7
5
7

Clinical Significance

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

Conservation

PhyloP100: 9.81
Variant links:
Genes affected
KLHL20 (HGNC:25056): (kelch like family member 20) The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 44-56 amino acid repeat motif. The kelch motif appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this family are present both throughout the cell and extracellularly, with diverse activities. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903
PP5
Variant 1-173757077-G-A is Pathogenic according to our data. Variant chr1-173757077-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 869211.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KLHL20NM_014458.4 linkuse as main transcriptc.1069G>A p.Gly357Arg missense_variant 7/12 ENST00000209884.5 NP_055273.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KLHL20ENST00000209884.5 linkuse as main transcriptc.1069G>A p.Gly357Arg missense_variant 7/121 NM_014458.4 ENSP00000209884 P1Q9Y2M5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 22, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 01, 2023This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 357 of the KLHL20 protein (p.Gly357Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KLHL20-related conditions (PMID: 29738522, 36214804). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 869211). 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 not expected to disrupt KLHL20 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterFeb 04, 2022PS4, PM2, PP2, PP3 -
Neurodevelopmental disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesMar 11, 2021- -
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGénétique des Maladies du Développement, Hospices Civils de Lyon-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Benign
-0.52
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-2.0
N
REVEL
Pathogenic
0.70
Sift
Benign
0.53
T
Sift4G
Benign
1.0
T
Polyphen
1.0
D
Vest4
0.93
MutPred
0.75
Gain of MoRF binding (P = 0.0064);
MVP
0.94
MPC
2.1
ClinPred
0.94
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.48
gMVP
0.84

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: rs1673582111; hg19: chr1-173726216; COSMIC: COSV52941802; API