Genetic Variant KLHL10:p.Val102Leu (chr17-41841932-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152467.5(KLHL10):c.304G>C(p.Val102Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V102M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLHL10
NM_152467.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.52

Publications

0 publications found

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]

KLHL10 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spermatogenic failure 11
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KLHL10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL10	NM_152467.5 link	c.304G>C	p.Val102Leu	missense_variant	Exon 2 of 5	ENST00000293303.5	NP_689680.2	Q6JEL2A0A140VJM8
KLHL10	NM_001329595.1 link	c.304G>C	p.Val102Leu	missense_variant	Exon 4 of 7		NP_001316524.1	Q6JEL2A0A140VJM8
KLHL10	NM_001329596.2 link	c.40G>C	p.Val14Leu	missense_variant	Exon 2 of 5		NP_001316525.1	Q6JEL2B4DX37
KLHL10	XM_047435897.1 link	c.304G>C	p.Val102Leu	missense_variant	Exon 3 of 6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL10	ENST00000293303.5 link	c.304G>C	p.Val102Leu	missense_variant	Exon 2 of 5	1	NM_152467.5	ENSP00000293303.4	Q6JEL2
KLHL10	ENST00000438813.1 link	c.286G>C	p.Val96Leu	missense_variant	Exon 2 of 2	4		ENSP00000416221.1	C9JHB3
KLHL10	ENST00000448203.2 link	c.304G>C	p.Val102Leu	missense_variant	Exon 4 of 4	4		ENSP00000391983.2	C9J999
KLHL10	ENST00000485613.1 link	n.350G>C		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.79

.;N;.

PhyloP100

4.5

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.26

Sift

Benign

0.15

.;T;D

Sift4G

Benign

0.63

T;T;T

Polyphen

0.99

.;D;.

Vest4

0.26

MutPred

0.60

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;

MVP

0.55

MPC

0.97

ClinPred

0.86

GERP RS

4.6

Varity_R

0.12

gMVP

0.75

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over