1-205338518-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018203.3(KLHDC8A):​c.836G>A​(p.Arg279Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,461,718 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000025 ( 1 hom. )

Consequence

KLHDC8A
NM_018203.3 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.79
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLHDC8ANM_018203.3 linkc.836G>A p.Arg279Gln missense_variant Exon 5 of 6 ENST00000367155.8 NP_060673.1 Q8IYD2A0A024R981

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLHDC8AENST00000367155.8 linkc.836G>A p.Arg279Gln missense_variant Exon 5 of 6 2 NM_018203.3 ENSP00000356123.3 Q8IYD2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251432
Hom.:
1
AF XY:
0.0000589
AC XY:
8
AN XY:
135892
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000490
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461718
Hom.:
1
Cov.:
30
AF XY:
0.0000275
AC XY:
20
AN XY:
727182
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:
0.000313
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000659
AC:
8

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.836G>A (p.R279Q) alteration is located in exon 5 (coding exon 4) of the KLHDC8A gene. This alteration results from a G to A substitution at nucleotide position 836, causing the arginine (R) at amino acid position 279 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
0.25
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T;T;T;.;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D;.;.;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.49
T;T;T;T;T
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Benign
1.4
L;L;L;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.5
N;N;N;.;.
REVEL
Uncertain
0.51
Sift
Benign
0.16
T;T;T;.;.
Sift4G
Benign
0.19
T;T;T;T;.
Polyphen
1.0
D;D;D;.;.
Vest4
0.80
MutPred
0.65
Loss of methylation at R279 (P = 0.0157);Loss of methylation at R279 (P = 0.0157);Loss of methylation at R279 (P = 0.0157);.;.;
MVP
0.88
MPC
1.2
ClinPred
0.60
D
GERP RS
4.7
Varity_R
0.27
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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: rs778546452; hg19: chr1-205307646; API