17-41845328-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_152467.5(KLHL10):​c.887T>C​(p.Ile296Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00797 in 1,614,174 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0056 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0082 ( 75 hom. )

Consequence

KLHL10
NM_152467.5 missense

Scores

11
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.62
Variant links:
Genes affected
KLHL10 (HGNC:18829): (kelch like family member 10) The protein encoded by this gene belongs to the kelch repeat-containing family, and contains an N-terminal BTB/POZ domain a BACK domain and six C-terminal kelch repeats. Kelch domains are thought to form a four stranded beta-sheet blade structure that can fold into a beta-propeller domain when multiple kelch repeats are found together. Mutations in this gene have been associated with oligozoospermia in some infertile males. [provided by RefSeq, Jul 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.01672268).
BP6
Variant 17-41845328-T-C is Benign according to our data. Variant chr17-41845328-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 684737.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
BS2
High AC in GnomAd4 at 850 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLHL10NM_152467.5 linkc.887T>C p.Ile296Thr missense_variant Exon 3 of 5 ENST00000293303.5 NP_689680.2 Q6JEL2A0A140VJM8
KLHL10NM_001329595.1 linkc.887T>C p.Ile296Thr missense_variant Exon 5 of 7 NP_001316524.1 Q6JEL2A0A140VJM8
KLHL10NM_001329596.2 linkc.623T>C p.Ile208Thr missense_variant Exon 3 of 5 NP_001316525.1 Q6JEL2B4DX37
KLHL10XM_047435897.1 linkc.887T>C p.Ile296Thr missense_variant Exon 4 of 6 XP_047291853.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLHL10ENST00000293303.5 linkc.887T>C p.Ile296Thr missense_variant Exon 3 of 5 1 NM_152467.5 ENSP00000293303.4 Q6JEL2

Frequencies

GnomAD3 genomes
AF:
0.00559
AC:
850
AN:
152188
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00157
Gnomad AMI
AF:
0.0164
Gnomad AMR
AF:
0.00379
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00330
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00966
Gnomad OTH
AF:
0.00527
GnomAD3 exomes
AF:
0.00546
AC:
1361
AN:
249422
Hom.:
5
AF XY:
0.00550
AC XY:
744
AN XY:
135322
show subpopulations
Gnomad AFR exome
AF:
0.00110
Gnomad AMR exome
AF:
0.00209
Gnomad ASJ exome
AF:
0.000695
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00186
Gnomad FIN exome
AF:
0.00251
Gnomad NFE exome
AF:
0.00999
Gnomad OTH exome
AF:
0.00380
GnomAD4 exome
AF:
0.00822
AC:
12014
AN:
1461868
Hom.:
75
Cov.:
32
AF XY:
0.00789
AC XY:
5739
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00140
Gnomad4 AMR exome
AF:
0.00246
Gnomad4 ASJ exome
AF:
0.000536
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00179
Gnomad4 FIN exome
AF:
0.00273
Gnomad4 NFE exome
AF:
0.0100
Gnomad4 OTH exome
AF:
0.00672
GnomAD4 genome
AF:
0.00558
AC:
850
AN:
152306
Hom.:
4
Cov.:
32
AF XY:
0.00485
AC XY:
361
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00156
Gnomad4 AMR
AF:
0.00379
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00330
Gnomad4 NFE
AF:
0.00966
Gnomad4 OTH
AF:
0.00522
Alfa
AF:
0.00743
Hom.:
1
Bravo
AF:
0.00568
TwinsUK
AF:
0.00755
AC:
28
ALSPAC
AF:
0.00856
AC:
33
ESP6500AA
AF:
0.00203
AC:
8
ESP6500EA
AF:
0.00759
AC:
63
ExAC
AF:
0.00615
AC:
744
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.00747
EpiControl
AF:
0.00859

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2025KLHL10: PP2, BS2 -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
Non-obstructive azoospermia Uncertain:1
Uncertain significance, criteria provided, single submitterresearchInstitute of Reproductive Genetics, University of MünsterJun 07, 2020- -
KLHL10-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 18, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.66
D
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
D
MetaRNN
Benign
0.017
T
MetaSVM
Benign
-0.63
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.4
D
REVEL
Uncertain
0.35
Sift
Benign
0.082
T
Sift4G
Benign
0.11
T
Polyphen
0.82
P
Vest4
0.74
MVP
0.42
MPC
0.94
ClinPred
0.049
T
GERP RS
6.2
Varity_R
0.74
gMVP
0.88

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: rs61752339; hg19: chr17-40001580; COSMIC: COSV99035591; COSMIC: COSV99035591; API