chr17-41842275-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_152467.5(KLHL10):ā€‹c.647A>Cā€‹(p.Gln216Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,614,166 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0035 ( 6 hom., cov: 31)
Exomes š‘“: 0.00037 ( 6 hom. )

Consequence

KLHL10
NM_152467.5 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:3

Conservation

PhyloP100: 0.528
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 -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005472094).
BP6
Variant 17-41842275-A-C is Benign according to our data. Variant chr17-41842275-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 40008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 527 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KLHL10NM_152467.5 linkc.647A>C p.Gln216Pro missense_variant 2/5 ENST00000293303.5 NP_689680.2 Q6JEL2A0A140VJM8
KLHL10NM_001329595.1 linkc.647A>C p.Gln216Pro missense_variant 4/7 NP_001316524.1 Q6JEL2A0A140VJM8
KLHL10NM_001329596.2 linkc.383A>C p.Gln128Pro missense_variant 2/5 NP_001316525.1 Q6JEL2B4DX37
KLHL10XM_047435897.1 linkc.647A>C p.Gln216Pro missense_variant 3/6 XP_047291853.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KLHL10ENST00000293303.5 linkc.647A>C p.Gln216Pro missense_variant 2/51 NM_152467.5 ENSP00000293303.4 Q6JEL2

Frequencies

GnomAD3 genomes
AF:
0.00347
AC:
528
AN:
152214
Hom.:
6
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0122
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000786
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:
0.0000441
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.000980
AC:
244
AN:
249080
Hom.:
3
AF XY:
0.000614
AC XY:
83
AN XY:
135234
show subpopulations
Gnomad AFR exome
AF:
0.0139
Gnomad AMR exome
AF:
0.000492
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:
0.000106
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000371
AC:
543
AN:
1461834
Hom.:
6
Cov.:
35
AF XY:
0.000322
AC XY:
234
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.0127
Gnomad4 AMR exome
AF:
0.000537
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.000762
GnomAD4 genome
AF:
0.00346
AC:
527
AN:
152332
Hom.:
6
Cov.:
31
AF XY:
0.00313
AC XY:
233
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0121
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.000643
Hom.:
1
Bravo
AF:
0.00388
ESP6500AA
AF:
0.00761
AC:
28
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00123
AC:
149
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Uncertain:1Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Spermatogenic failure 11 Pathogenic:1Uncertain:1Benign:1
Uncertain significance, no assertion criteria providedcurationReproductive Health Research and Development, BGI GenomicsJan 06, 2020NM_152467.3:c.647A>C in the KLHL10 gene has an allele frequency of 0.013 in African subpopulation in the gnomAD database. This variant has been detected in four individual with oligozoospermia (PMID: 17047026). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, PP4. -
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 02, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2006- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
15
DANN
Benign
0.94
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.57
T
MetaRNN
Benign
0.0055
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.64
N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.15
Sift
Benign
0.27
T
Sift4G
Benign
0.27
T
Polyphen
0.0010
B
Vest4
0.69
MVP
0.43
MPC
0.75
ClinPred
0.0045
T
GERP RS
2.1
Varity_R
0.42
gMVP
0.59

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: rs116420871; hg19: chr17-39998527; API