Variant 4-87170237-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000273963.10(KLHL8):c.1379A>G(p.Asn460Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KLHL8
ENST00000273963.10 missense, splice_region

Scores

Splicing: ADA: 0.0001247

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Variant links:

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]

KLHL8 links:

KLHL8 (HGNC:):

KLHL8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28107625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL8	NM_020803.5 linkuse as main transcript	c.1379A>G	p.Asn460Ser	missense_variant, splice_region_variant	8/10	ENST00000273963.10	NP_065854.3	Q9P2G9-1Q7Z330

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL8	ENST00000273963.10 linkuse as main transcript	c.1379A>G	p.Asn460Ser	missense_variant, splice_region_variant	8/10	1	NM_020803.5	ENSP00000273963.5		Q9P2G9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1454482

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Aug 22, 2023

The c.1379A>G (p.N460S) alteration is located in exon 8 (coding exon 7) of the KLHL8 gene. This alteration results from a A to G substitution at nucleotide position 1379, causing the asparagine (N) at amino acid position 460 to be replaced by a serine (S). 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

0.064

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;.;.;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.88

D;D;D;.

M_CAP

Benign

0.029

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.1

M;.;.;M

MutationTaster

Benign

0.97

D;D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.88

N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.071

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.22

MutPred

0.71

Gain of glycosylation at Y463 (P = 0.0178);.;.;Gain of glycosylation at Y463 (P = 0.0178);

MVP

0.74

MPC

0.34

ClinPred

0.10

GERP RS

1.9

Varity_R

0.058

gMVP

0.096

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.012

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