Variant 1-205339724-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_018203.3(KLHDC8A):c.461T>C(p.Met154Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KLHDC8A
NM_018203.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70

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:

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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=0.3215248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC8A	NM_018203.3 linkuse as main transcript	c.461T>C	p.Met154Thr	missense_variant	3/6	ENST00000367155.8	NP_060673.1	Q8IYD2A0A024R981

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC8A	ENST00000367155.8 linkuse as main transcript	c.461T>C	p.Met154Thr	missense_variant	3/6	2	NM_018203.3	ENSP00000356123.3		Q8IYD2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

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:

0.0000187

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Apr 22, 2022

The c.461T>C (p.M154T) alteration is located in exon 3 (coding exon 2) of the KLHDC8A gene. This alteration results from a T to C substitution at nucleotide position 461, causing the methionine (M) at amino acid position 154 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

0.19

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.027

T;T;T;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.040

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.79

T;.;.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.46

N;N;N;.;.

MutationTaster

Benign

0.96

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.59

N;N;N;.;.

REVEL

Benign

0.14

Sift

Benign

0.43

T;T;T;.;.

Sift4G

Benign

0.47

T;T;T;T;.

Polyphen

0.010

B;B;B;.;.

Vest4

0.52

MutPred

0.34

Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);.;.;

MVP

0.71

MPC

0.50

ClinPred

0.64

GERP RS

5.9

Varity_R

0.28

gMVP

0.17

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over