6-43017692-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_057161.4(KLHDC3):​c.328G>A​(p.Val110Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,610,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

KLHDC3
NM_057161.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06675315).
BS2
High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KLHDC3NM_057161.4 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 3/11 ENST00000326974.9 NP_476502.1 Q9BQ90
KLHDC3XM_047418163.1 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 3/11 XP_047274119.1
KLHDC3XM_047418164.1 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 3/11 XP_047274120.1
KLHDC3NR_040101.2 linkuse as main transcriptn.487G>A non_coding_transcript_exon_variant 3/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KLHDC3ENST00000326974.9 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 3/111 NM_057161.4 ENSP00000313995.4 Q9BQ90
KLHDC3ENST00000244670.12 linkuse as main transcriptc.42G>A p.Thr14Thr synonymous_variant 3/101 ENSP00000244670.8 F8W6A4

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000221
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000113
AC:
28
AN:
248122
Hom.:
0
AF XY:
0.000142
AC XY:
19
AN XY:
134028
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000586
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000994
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000196
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000118
AC:
172
AN:
1458418
Hom.:
0
Cov.:
31
AF XY:
0.000106
AC XY:
77
AN XY:
725234
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000450
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000139
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152290
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
15
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000517
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000165
AC:
20

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 submitterclinical testingAmbry GeneticsDec 04, 2024The c.328G>A (p.V110I) alteration is located in exon 3 (coding exon 2) of the KLHDC3 gene. This alteration results from a G to A substitution at nucleotide position 328, causing the valine (V) at amino acid position 110 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
0.082
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.12
T;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.00096
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.067
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.20
N;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.77
N;.
REVEL
Benign
0.040
Sift
Benign
0.42
T;.
Sift4G
Benign
0.52
T;T
Polyphen
0.0020
B;.
Vest4
0.20
MVP
0.43
MPC
0.88
ClinPred
0.030
T
GERP RS
4.3
Varity_R
0.055
gMVP
0.53

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.

Other links and lift over

dbSNP: rs115973150; hg19: chr6-42985430; COSMIC: COSV55065443; COSMIC: COSV55065443; API