1-205339667-C-T

Variant names:

• chr1-205339667-C-T
• rs775351217
• NM_018203.3:c.518G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018203.3(KLHDC8A):​c.518G>A​(p.Arg173Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: 0.000014 (0 hom.)
• Consequence: KLHDC8A NM_018203.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32184115).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018203.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC8A	NM_018203.3	MANE Select	c.518G>A	p.Arg173Gln	missense	Exon 3 of 6	NP_060673.1	Q8IYD2
	KLHDC8A	NM_001271863.2		c.518G>A	p.Arg173Gln	missense	Exon 6 of 9	NP_001258792.1	Q8IYD2
	KLHDC8A	NM_001271864.2		c.518G>A	p.Arg173Gln	missense	Exon 4 of 7	NP_001258793.1	Q8IYD2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC8A	ENST00000367155.8	TSL:2 MANE Select	c.518G>A	p.Arg173Gln	missense	Exon 3 of 6	ENSP00000356123.3	Q8IYD2
	KLHDC8A	ENST00000941910.1		c.518G>A	p.Arg173Gln	missense	Exon 3 of 6	ENSP00000611969.1
	KLHDC8A	ENST00000367156.7	TSL:2	c.518G>A	p.Arg173Gln	missense	Exon 6 of 9	ENSP00000356124.3	Q8IYD2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251354 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111976

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.28
Sift	Benign	0.27	T
Sift4G	Benign	0.44	T
Polyphen		1.0	D
Vest4		0.32
MutPred		0.63		Loss of MoRF binding (P = 0.0154)
MVP		0.85
MPC		0.52
ClinPred		0.33	T
GERP RS		5.9
PromoterAI		-0.013	Neutral
Varity_R		0.12
gMVP		0.57
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775351217; hg19: chr1-205308795; COSMIC: COSV100903861; COSMIC: COSV100903861;