chr6-43019115-G-A

Position:

• chr6-43019115-G-A

Variant summary

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

The ENST00000326974.9(KLHDC3):​c.953G>A​(p.Gly318Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHDC3 ENST00000326974.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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]

KLHDC3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC3	NM_057161.4	c.953G>A	p.Gly318Glu	missense_variant	9/11	ENST00000326974.9	NP_476502.1
KLHDC3	XM_047418163.1	c.953G>A	p.Gly318Glu	missense_variant	9/11		XP_047274119.1
KLHDC3	XM_047418164.1	c.953G>A	p.Gly318Glu	missense_variant	9/11		XP_047274120.1
KLHDC3	NR_040101.2	n.996G>A		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC3	ENST00000326974.9	c.953G>A	p.Gly318Glu	missense_variant	9/11	1	NM_057161.4	ENSP00000313995.4
KLHDC3	ENST00000244670.12	c.551G>A	p.Gly184Glu	missense_variant	8/10	1		ENSP00000244670.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Mar 16, 2024

The c.953G>A (p.G318E) alteration is located in exon 9 (coding exon 8) of the KLHDC3 gene. This alteration results from a G to A substitution at nucleotide position 953, causing the glycine (G) at amino acid position 318 to be replaced by a glutamic acid (E). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.21	.;T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.26
Sift	Benign	0.66	T;T;.
Sift4G	Benign	0.63	T;T;T
Polyphen		0.98	D;P;.
Vest4		0.68
MutPred		0.42		.;Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.88
MPC		1.8
ClinPred		0.52	D
GERP RS		5.5
Varity_R		0.086
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-42986853;