chr17-41845328-T-C

Position:

chr17-41845328-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The ENST00000293303.5(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
ENST00000293303.5 missense

Scores

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]

KLHL10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 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=0.01672268).

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: {Benign=1, Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 850 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL10	NM_152467.5 linkuse as main transcript	c.887T>C	p.Ile296Thr	missense_variant	3/5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1 linkuse as main transcript	c.887T>C	p.Ile296Thr	missense_variant	5/7		NP_001316524.1
KLHL10	NM_001329596.2 linkuse as main transcript	c.623T>C	p.Ile208Thr	missense_variant	3/5		NP_001316525.1
KLHL10	XM_047435897.1 linkuse as main transcript	c.887T>C	p.Ile296Thr	missense_variant	4/6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000293303.5 linkuse as main transcript	c.887T>C	p.Ile296Thr	missense_variant	3/5	1	NM_152467.5	ENSP00000293303	P1

Frequencies

GnomAD3 genomes

AF:

0.00559

AC:

850

AN:

152188

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00568

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00203

AC:

ESP6500EA

AF:

0.00759

AC:

ExAC

AF:

0.00615

AC:

744

Asia WGS

AF:

0.00144

AC:

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	KLHL10: BS2 -

Non-obstructive azoospermia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Institute of Reproductive Genetics, University of Münster

Jun 07, 2020

- -

KLHL10-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

This 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

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.35

Sift

Benign

0.082

Sift4G

Benign

0.11

Polyphen

0.82

Vest4

0.74

MVP

0.42

MPC

0.94

ClinPred

0.049

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.

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