1-161098633-G-A

Position:

• chr1-161098633-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152366.5(KLHDC9):​c.98G>A​(p.Cys33Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHDC9 NM_152366.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40

Genes affected

KLHDC9 (HGNC:28489): (kelch domain containing 9) Enables cyclin binding activity. [provided by Alliance of Genome Resources, Apr 2022]

KLHDC9 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC9	NM_152366.5	c.98G>A	p.Cys33Tyr	missense_variant	1/4	ENST00000368011.9	NP_689579.3
KLHDC9	NM_001007255.3	c.98G>A	p.Cys33Tyr	missense_variant	1/4		NP_001007256.1
KLHDC9	NR_033385.2	n.45-33G>A		intron_variant
KLHDC9	NR_033386.2	n.45-33G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC9	ENST00000368011.9	c.98G>A	p.Cys33Tyr	missense_variant	1/4	1	NM_152366.5	ENSP00000356990.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459092 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725738

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.98G>A (p.C33Y) alteration is located in exon 1 (coding exon 1) of the KLHDC9 gene. This alteration results from a G to A substitution at nucleotide position 98, causing the cysteine (C) at amino acid position 33 to be replaced by a tyrosine (Y). 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.78
MVP		0.44
MPC		1.4
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-161068423;