4-87178492-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020803.5(KLHL8):c.1081G>T(p.Val361Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,609,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
KLHL8
NM_020803.5 missense
NM_020803.5 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 7.72
Genes affected
KLHL8 (HGNC:18644): (kelch like family member 8) Involved in protein ubiquitination and ubiquitin-dependent protein catabolic process. Located in nucleoplasm. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL8 | NM_020803.5 | c.1081G>T | p.Val361Leu | missense_variant | 5/10 | ENST00000273963.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL8 | ENST00000273963.10 | c.1081G>T | p.Val361Leu | missense_variant | 5/10 | 1 | NM_020803.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247124Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133754
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GnomAD4 exome AF: 0.00000686 AC: 10AN: 1457808Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5AN XY: 725208
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
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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 submitter | clinical testing | Ambry Genetics | Apr 27, 2023 | The c.1081G>T (p.V361L) alteration is located in exon 5 (coding exon 4) of the KLHL8 gene. This alteration results from a G to T substitution at nucleotide position 1081, causing the valine (V) at amino acid position 361 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;.;N
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N;D;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;T;D;D
Polyphen
D;.;B;D
Vest4
MutPred
Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at