chr17-41842082-T-C

Position:

chr17-41842082-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_152467.5(KLHL10):c.454T>C(p.Tyr152His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,030 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 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

KLHL10
NM_152467.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.504

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:

KLHL10 (HGNC:):

KLHL10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KLHL10. . Gene score misZ 2.7236 (greater than the threshold 3.09). Trascript score misZ 4.4991 (greater than threshold 3.09). GenCC has associacion of gene with male infertility with azoospermia or oligozoospermia due to single gene mutation.

BP4

Computational evidence support a benign effect (MetaRNN=0.18840453).

BS2

High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL10	NM_152467.5 linkuse as main transcript	c.454T>C	p.Tyr152His	missense_variant	2/5	ENST00000293303.5	NP_689680.2	Q6JEL2A0A140VJM8
KLHL10	NM_001329595.1 linkuse as main transcript	c.454T>C	p.Tyr152His	missense_variant	4/7		NP_001316524.1	Q6JEL2A0A140VJM8
KLHL10	NM_001329596.2 linkuse as main transcript	c.190T>C	p.Tyr64His	missense_variant	2/5		NP_001316525.1	Q6JEL2B4DX37
KLHL10	XM_047435897.1 linkuse as main transcript	c.454T>C	p.Tyr152His	missense_variant	3/6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL10	ENST00000293303.5 linkuse as main transcript	c.454T>C	p.Tyr152His	missense_variant	2/5	1	NM_152467.5	ENSP00000293303.4	Q6JEL2
KLHL10	ENST00000438813.1 linkuse as main transcript	c.436T>C	p.Tyr146His	missense_variant	2/2	4		ENSP00000416221.1	C9JHB3
KLHL10	ENST00000485613.1 linkuse as main transcript	n.500T>C		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249582

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

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 submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.454T>C (p.Y152H) alteration is located in exon 2 (coding exon 2) of the KLHL10 gene. This alteration results from a T to C substitution at nucleotide position 454, causing the tyrosine (Y) at amino acid position 152 to be replaced by a histidine (H). 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

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-0.51

N;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.5

D;N

REVEL

Benign

0.18

Sift

Benign

0.28

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0020

B;.

Vest4

0.10

MutPred

0.56

Loss of helix (P = 0.1299);.;

MVP

0.34

MPC

0.80

ClinPred

0.062

GERP RS

5.7

Varity_R

0.10

gMVP

0.45

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