17-41837952-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152467.5(KLHL10):c.20C>T(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KLHL10
NM_152467.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2465539).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL10	NM_152467.5 link	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 5	ENST00000293303.5	NP_689680.2	Q6JEL2A0A140VJM8
KLHL10	NM_001329595.1 link	c.20C>T	p.Ala7Val	missense_variant	Exon 3 of 7		NP_001316524.1	Q6JEL2A0A140VJM8
KLHL10	XM_047435897.1 link	c.20C>T	p.Ala7Val	missense_variant	Exon 2 of 6		XP_047291853.1
KLHL10	NM_001329596.2 link	c.-183C>T		5_prime_UTR_variant	Exon 1 of 5		NP_001316525.1	Q6JEL2B4DX37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL10	ENST00000293303.5 link	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 5	1	NM_152467.5	ENSP00000293303.4	Q6JEL2
KLHL10	ENST00000438813.1 link	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 2	4		ENSP00000416221.1	C9JHB3
KLHL10	ENST00000448203.2 link	c.20C>T	p.Ala7Val	missense_variant	Exon 3 of 4	4		ENSP00000391983.2	C9J999
KLHL10	ENST00000485613.1 link	n.128C>T		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249522

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20C>T (p.A7V) alteration is located in exon 1 (coding exon 1) of the KLHL10 gene. This alteration results from a C to T substitution at nucleotide position 20, causing the alanine (A) at amino acid position 7 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0062

T;T;T

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.66

T;T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.55

.;N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.020

D;D;D

Sift4G

Uncertain

0.031

D;T;D

Polyphen

0.99

.;D;.

Vest4

0.24

MutPred

0.18

Gain of catalytic residue at A7 (P = 0.0356);Gain of catalytic residue at A7 (P = 0.0356);Gain of catalytic residue at A7 (P = 0.0356);

MVP

0.63

MPC

0.61

ClinPred

0.37

GERP RS

4.7

Varity_R

0.069

gMVP

0.57

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