1-161098800-G-C

Variant names:

• chr1-161098800-G-C
• rs1571175839
• NM_152366.5:c.265G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152366.5(KLHDC9):​c.265G>C​(p.Gly89Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,374 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: 7.0e-7 (0 hom.)
• Consequence: KLHDC9 NM_152366.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

Genes affected

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

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=0.22645509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC9	NM_152366.5	c.265G>C	p.Gly89Arg	missense_variant	Exon 1 of 4	ENST00000368011.9	NP_689579.3
KLHDC9	NM_001007255.3	c.265G>C	p.Gly89Arg	missense_variant	Exon 1 of 4		NP_001007256.1
KLHDC9	NR_033385.2	n.179G>C		non_coding_transcript_exon_variant	Exon 2 of 5
KLHDC9	NR_033386.2	n.179G>C		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC9	ENST00000368011.9	c.265G>C	p.Gly89Arg	missense_variant	Exon 1 of 4	1	NM_152366.5	ENSP00000356990.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436374 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712522

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265G>C (p.G89R) alteration is located in exon 1 (coding exon 1) of the KLHDC9 gene. This alteration results from a G to C substitution at nucleotide position 265, causing the glycine (G) at amino acid position 89 to be replaced by an arginine (R). 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	0.15
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.0067
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.23
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.032	B;D
Vest4		0.38
MutPred		0.47		Gain of MoRF binding (P = 0.0202);Gain of MoRF binding (P = 0.0202);
MVP		0.81
MPC		1.1
ClinPred		0.97	D
GERP RS		3.1
Varity_R		0.19
gMVP		0.66

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: rs1571175839; hg19: chr1-161068590;