1-205337431-C-T

Variant names:

• chr1-205337431-C-T
• rs778433451
• NM_018203.3:c.1021G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

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]

ACMG classification

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
KLHDC8A	NM_018203.3	c.1021G>A	p.Ala341Thr	missense_variant	Exon 6 of 6	ENST00000367155.8	NP_060673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC8A	ENST00000367155.8	c.1021G>A	p.Ala341Thr	missense_variant	Exon 6 of 6	2	NM_018203.3	ENSP00000356123.3

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

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

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

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

Other links and lift over

dbSNP: rs778433451; hg19: chr1-205306559;