rs2295982

Positions:

• chr6-43017099-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_057161.4(KLHDC3):​c.-59-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,440,342 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0047 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (257 hom.)
• Consequence: KLHDC3 NM_057161.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.313

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 Benign. Variant got -12 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 0 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC3	NM_057161.4	c.-59-35C>T		intron_variant		ENST00000326974.9	NP_476502.1
KLHDC3	XM_047418163.1	c.-59-35C>T		intron_variant			XP_047274119.1
KLHDC3	XM_047418164.1	c.-59-35C>T		intron_variant			XP_047274120.1
KLHDC3	NR_040101.2	n.101-35C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC3	ENST00000326974.9	c.-59-35C>T		intron_variant		1	NM_057161.4	ENSP00000313995	P1
KLHDC3	ENST00000244670.12	c.-345-35C>T		intron_variant		1		ENSP00000244670

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 715 AN: 152150 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00392 AC: 5053 AN: 1288074 Hom.: 257 Cov.: 19 AF XY: 0.00374 AC XY: 2392 AN XY: 640030

Gnomad4 AFR exome AF: 0.000231

Gnomad4 AMR exome AF: 0.000352

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.00339

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.00524

GnomAD4 genome AF: 0.00468 AC: 712 AN: 152268 Hom.: 35 Cov.: 32 AF XY: 0.00516 AC XY: 384 AN XY: 74456

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00177 Hom.: 3

Bravo AF: 0.00472

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	5.2
DANN	Benign	0.64
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2295982; hg19: chr6-42984837;