chr1-205339206-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018203.3(KLHDC8A):​c.745G>T​(p.Asp249Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D249N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLHDC8A
NM_018203.3 missense

Scores

7
10
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.89
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLHDC8ANM_018203.3 linkc.745G>T p.Asp249Tyr missense_variant Exon 4 of 6 ENST00000367155.8 NP_060673.1 Q8IYD2A0A024R981

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLHDC8AENST00000367155.8 linkc.745G>T p.Asp249Tyr missense_variant Exon 4 of 6 2 NM_018203.3 ENSP00000356123.3 Q8IYD2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461678
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727160
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;T;T;.;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D;.;.;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Uncertain
2.2
M;M;M;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-7.1
D;D;D;.;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
D;D;D;.;.
Sift4G
Uncertain
0.0040
D;D;D;D;.
Polyphen
1.0
D;D;D;.;.
Vest4
0.96
MutPred
0.62
Gain of phosphorylation at D249 (P = 0.0206);Gain of phosphorylation at D249 (P = 0.0206);Gain of phosphorylation at D249 (P = 0.0206);.;.;
MVP
0.95
MPC
1.4
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.91
gMVP
0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-205308334; API