Genetic Variant KLHDC8A:p.Arg279Gln (chr1-205338518-C-T) – ACMG Classification: Uncertain_significance (2 pts)

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

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]

KLHDC8A links:

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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
KLHDC8A	NM_018203.3 link	c.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
KLHDC8A	ENST00000367155.8 link	c.836G>A	p.Arg279Gln	missense_variant	Exon 5 of 6	2	NM_018203.3	ENSP00000356123.3		Q8IYD2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251432

Hom.:

AF XY:

0.0000589

AC XY:

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:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

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.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000659

AC:

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

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

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

LIST_S2

Uncertain

0.94

D;.;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.4

L;L;L;.;.

PrimateAI

Uncertain

0.62

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

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.

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