1-205337431-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018203.3(KLHDC8A):​c.1021G>A​(p.Ala341Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

KLHDC8A
NM_018203.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.76
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21736592).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLHDC8ANM_018203.3 linkc.1021G>A p.Ala341Thr missense_variant Exon 6 of 6 ENST00000367155.8 NP_060673.1 Q8IYD2A0A024R981

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLHDC8AENST00000367155.8 linkc.1021G>A p.Ala341Thr missense_variant Exon 6 of 6 2 NM_018203.3 ENSP00000356123.3 Q8IYD2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251434
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000527
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461368
Hom.:
0
Cov.:
30
AF XY:
0.0000124
AC XY:
9
AN XY:
726996
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1021G>A (p.A341T) alteration is located in exon 6 (coding exon 5) of the KLHDC8A gene. This alteration results from a G to A substitution at nucleotide position 1021, causing the alanine (A) at amino acid position 341 to be replaced by a threonine (T). 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
0.13
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.065
T;T;T;.
Eigen
Benign
0.052
Eigen_PC
Benign
0.035
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.83
T;.;.;T
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.22
T;T;T;T
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Uncertain
2.1
M;M;M;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.6
N;N;N;.
REVEL
Benign
0.16
Sift
Benign
0.11
T;T;T;.
Sift4G
Benign
0.16
T;T;T;T
Polyphen
1.0
D;D;D;.
Vest4
0.19
MutPred
0.37
Gain of glycosylation at A341 (P = 0.1475);Gain of glycosylation at A341 (P = 0.1475);Gain of glycosylation at A341 (P = 0.1475);.;
MVP
0.78
MPC
0.78
ClinPred
0.26
T
GERP RS
4.5
Varity_R
0.093
gMVP
0.56

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: rs778433451; hg19: chr1-205306559; API