6-43017551-A-C

Variant names:

• chr6-43017551-A-C
• rs1349660508
• NM_057161.4:c.187A>C

Variant summary

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

The NM_057161.4(KLHDC3):​c.187A>C​(p.Lys63Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: KLHDC3 NM_057161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16955304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC3	NM_057161.4	c.187A>C	p.Lys63Gln	missense_variant	Exon 3 of 11	ENST00000326974.9	NP_476502.1
KLHDC3	XM_047418163.1	c.187A>C	p.Lys63Gln	missense_variant	Exon 3 of 11		XP_047274119.1
KLHDC3	XM_047418164.1	c.187A>C	p.Lys63Gln	missense_variant	Exon 3 of 11		XP_047274120.1
KLHDC3	NR_040101.2	n.346A>C		non_coding_transcript_exon_variant	Exon 3 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC3	ENST00000326974.9	c.187A>C	p.Lys63Gln	missense_variant	Exon 3 of 11	1	NM_057161.4	ENSP00000313995.4
KLHDC3	ENST00000244670	c.-100A>C		5_prime_UTR_variant	Exon 3 of 10	1		ENSP00000244670.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187A>C (p.K63Q) alteration is located in exon 3 (coding exon 2) of the KLHDC3 gene. This alteration results from a A to C substitution at nucleotide position 187, causing the lysine (K) at amino acid position 63 to be replaced by a glutamine (Q). 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	0.089
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.59	N;.
REVEL	Benign	0.12
Sift	Benign	0.44	T;.
Sift4G	Benign	0.48	T;T
Polyphen		0.049	B;.
Vest4		0.25
MutPred		0.51		Loss of ubiquitination at K63 (P = 0.0381);Loss of ubiquitination at K63 (P = 0.0381);
MVP		0.71
MPC		1.1
ClinPred		0.18	T
GERP RS		2.9
Varity_R		0.050
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1349660508; hg19: chr6-42985289;