3-47330118-G-A

Variant summary

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

The NM_025010.5(KLHL18):​c.569G>A​(p.Arg190Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

KLHL18
NM_025010.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.53
Variant links:
Genes affected
KLHL18 (HGNC:29120): (kelch like family member 18) Involved in positive regulation of mitotic cell cycle phase transition and protein ubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2354244).
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KLHL18NM_025010.5 linkc.569G>A p.Arg190Gln missense_variant 4/10 ENST00000232766.6 NP_079286.2 O94889-1A0A024R2T4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KLHL18ENST00000232766.6 linkc.569G>A p.Arg190Gln missense_variant 4/101 NM_025010.5 ENSP00000232766.5 O94889-1
KLHL18ENST00000442272.1 linkn.*258G>A non_coding_transcript_exon_variant 3/92 ENSP00000392507.1 F8WCL4
KLHL18ENST00000461084.5 linkn.589G>A non_coding_transcript_exon_variant 4/72
KLHL18ENST00000442272.1 linkn.*258G>A 3_prime_UTR_variant 3/92 ENSP00000392507.1 F8WCL4

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251392
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461870
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000936
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 01, 2024The c.569G>A (p.R190Q) alteration is located in exon 4 (coding exon 4) of the KLHL18 gene. This alteration results from a G to A substitution at nucleotide position 569, causing the arginine (R) at amino acid position 190 to be replaced by a glutamine (Q). 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
Benign
0.12
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.24
T
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
1.7
L
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.21
Sift
Benign
0.17
T
Sift4G
Benign
0.38
T
Polyphen
0.030
B
Vest4
0.24
MutPred
0.59
Loss of phosphorylation at S189 (P = 0.1299);
MVP
0.39
MPC
0.73
ClinPred
0.20
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
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: rs780179955; hg19: chr3-47371608; API