6-43019324-T-C

Variant names:

• chr6-43019324-T-C
• rs1354378448
• NM_057161.4:c.1040T>C

Variant summary

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

The NM_057161.4(KLHDC3):​c.1040T>C​(p.Ile347Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHDC3 NM_057161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC3	NM_057161.4	c.1040T>C	p.Ile347Thr	missense_variant	Exon 10 of 11	ENST00000326974.9	NP_476502.1
KLHDC3	XM_047418163.1	c.1040T>C	p.Ile347Thr	missense_variant	Exon 10 of 11		XP_047274119.1
KLHDC3	XM_047418164.1	c.1040T>C	p.Ile347Thr	missense_variant	Exon 10 of 11		XP_047274120.1
KLHDC3	NR_040101.2	n.1083T>C		non_coding_transcript_exon_variant	Exon 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC3	ENST00000326974.9	c.1040T>C	p.Ile347Thr	missense_variant	Exon 10 of 11	1	NM_057161.4	ENSP00000313995.4
KLHDC3	ENST00000244670.12	c.638T>C	p.Ile213Thr	missense_variant	Exon 9 of 10	1		ENSP00000244670.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

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

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1040T>C (p.I347T) alteration is located in exon 10 (coding exon 9) of the KLHDC3 gene. This alteration results from a T to C substitution at nucleotide position 1040, causing the isoleucine (I) at amino acid position 347 to be replaced by a threonine (T). 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	0.85
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	.;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;D;.
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.63	P;B;.
Vest4		0.79
MutPred		0.51		.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.31
MPC		1.6
ClinPred		0.83	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.95

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: rs1354378448; hg19: chr6-42987062;