Variant 6-43017256-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000326974.9(KLHDC3):c.64G>A(p.Val22Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

KLHDC3
ENST00000326974.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.51

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33945012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHDC3	NM_057161.4 linkuse as main transcript	c.64G>A	p.Val22Ile	missense_variant	2/11	ENST00000326974.9	NP_476502.1
KLHDC3	XM_047418163.1 linkuse as main transcript	c.64G>A	p.Val22Ile	missense_variant	2/11		XP_047274119.1
KLHDC3	XM_047418164.1 linkuse as main transcript	c.64G>A	p.Val22Ile	missense_variant	2/11		XP_047274120.1
KLHDC3	NR_040101.2 linkuse as main transcript	n.223G>A		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC3	ENST00000326974.9 linkuse as main transcript	c.64G>A	p.Val22Ile	missense_variant	2/11	1	NM_057161.4	ENSP00000313995	P1
KLHDC3	ENST00000244670.12 linkuse as main transcript	c.-223G>A		5_prime_UTR_variant	2/10	1		ENSP00000244670

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.64G>A (p.V22I) alteration is located in exon 2 (coding exon 1) of the KLHDC3 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the valine (V) at amino acid position 22 to be replaced by an isoleucine (I). 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

0.10

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

T;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.80

N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.15

Sift

Benign

0.38

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.14

B;B

Vest4

0.59

MutPred

0.61

Loss of MoRF binding (P = 0.1135);Loss of MoRF binding (P = 0.1135);

MVP

0.44

MPC

1.1

ClinPred

0.91

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over