Variant 1-205343586-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018203.3(KLHDC8A):c.19A>G(p.Lys7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,605,750 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 0.00071 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 0 hom. )

Consequence

KLHDC8A
NM_018203.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33

Variant links:

Genes affected

KLHDC8A (HGNC:25573): (kelch domain containing 8A) This gene encodes a kelch domain-containing protein which is upregulated in cancer. Upregulated expression of the encoded protein may provide an alternative pathway for tumors to maintain aggressiveness in the absence of epidermal growth factor receptor dependence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

KLHDC8A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010540426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC8A	NM_018203.3 linkuse as main transcript	c.19A>G	p.Lys7Glu	missense_variant	2/6	ENST00000367155.8	NP_060673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC8A	ENST00000367155.8 linkuse as main transcript	c.19A>G	p.Lys7Glu	missense_variant	2/6	2	NM_018203.3	ENSP00000356123	P1

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000549

AC:

132

AN:

240324

Hom.:

AF XY:

0.000547

AC XY:

AN XY:

131548

show subpopulations

Gnomad AFR exome

AF:

0.000268

Gnomad AMR exome

AF:

0.000412

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.000916

Gnomad NFE exome

AF:

0.000804

Gnomad OTH exome

AF:

0.000683

GnomAD4 exome

AF:

0.000805

AC:

1170

AN:

1453434

Hom.:

Cov.:

AF XY:

0.000794

AC XY:

573

AN XY:

721830

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000519

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.000964

Gnomad4 OTH exome

AF:

0.000284

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152316

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000813

Hom.:

Bravo

AF:

0.000816

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000421

AC:

EpiCase

AF:

0.00142

EpiControl

AF:

0.00131

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 02, 2021

The c.19A>G (p.K7E) alteration is located in exon 2 (coding exon 1) of the KLHDC8A gene. This alteration results from a A to G substitution at nucleotide position 19, causing the lysine (K) at amino acid position 7 to be replaced by a glutamic acid (E). 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

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.044

T;T;T;.;.;.

Eigen

Benign

-0.069

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.73

T;.;.;T;T;T

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.2

L;L;L;.;.;.

MutationTaster

Benign

0.77

D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.76

N;N;N;.;.;.

REVEL

Benign

0.069

Sift

Benign

0.036

D;D;D;.;.;.

Sift4G

Benign

0.11

T;T;T;D;D;.

Polyphen

0.039

B;B;B;.;.;.

Vest4

0.15

MVP

0.75

MPC

0.66

ClinPred

0.011

GERP RS

5.5

Varity_R

0.24

gMVP

0.71

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.

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