6-43018932-G-C

Variant names:

• chr6-43018932-G-C
• NM_057161.4:c.890G>C

Variant summary

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

The NM_057161.4(KLHDC3):​c.890G>C​(p.Cys297Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: KLHDC3 NM_057161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21

Genes affected

KLHDC3 (HGNC:20704): (kelch domain containing 3) The protein encoded by this gene contains six repeated kelch motifs that are structurally similar to recombination activating gene 2, a protein involved in the activation of the V(D)J recombination. In mouse, this gene is found to be expressed specifically in testis. Its expression in pachytene spermatocytes is localized to cytoplasma and meiotic chromatin, suggesting that this gene may be involved in meiotic recombination. [provided by RefSeq, Jun 2012]

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, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC3	NM_057161.4	c.890G>C	p.Cys297Ser	missense_variant	Exon 8 of 11	ENST00000326974.9	NP_476502.1
KLHDC3	XM_047418163.1	c.890G>C	p.Cys297Ser	missense_variant	Exon 8 of 11		XP_047274119.1
KLHDC3	XM_047418164.1	c.890G>C	p.Cys297Ser	missense_variant	Exon 8 of 11		XP_047274120.1
KLHDC3	NR_040101.2	n.933G>C		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC3	ENST00000326974.9	c.890G>C	p.Cys297Ser	missense_variant	Exon 8 of 11	1	NM_057161.4	ENSP00000313995.4
KLHDC3	ENST00000244670.12	c.488G>C	p.Cys163Ser	missense_variant	Exon 7 of 10	1		ENSP00000244670.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.890G>C (p.C297S) alteration is located in exon 8 (coding exon 7) of the KLHDC3 gene. This alteration results from a G to C substitution at nucleotide position 890, causing the cysteine (C) at amino acid position 297 to be replaced by a serine (S). 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	0.78
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	.;D;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	2.0	.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D;D;.
REVEL	Uncertain	0.58
Sift	Benign	0.093	T;T;.
Sift4G	Benign	0.22	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.81
MutPred		0.68		.;Loss of stability (P = 0.0387);Loss of stability (P = 0.0387);
MVP		0.42
MPC		2.5
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr6-42986670;