rs370756367

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152467.5(KLHL10):c.937G>A(p.Ala313Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

KLHL10
NM_152467.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 1.41

Publications

3 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13597953).

BS2

High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KLHL10	NM_152467.5 link	c.937G>A	p.Ala313Thr	missense_variant	Exon 3 of 5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1 link	c.937G>A	p.Ala313Thr	missense_variant	Exon 5 of 7		NP_001316524.1
KLHL10	NM_001329596.2 link	c.673G>A	p.Ala225Thr	missense_variant	Exon 3 of 5		NP_001316525.1
KLHL10	XM_047435897.1 link	c.937G>A	p.Ala313Thr	missense_variant	Exon 4 of 6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000293303.5 link	c.937G>A	p.Ala313Thr	missense_variant	Exon 3 of 5	1	NM_152467.5	ENSP00000293303.4

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152204

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:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000353

AC:

AN:

249448

AF XY:

0.000347

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000389

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.000477

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000267

AC:

391

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39698

South Asian (SAS)

AF:

0.000684

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000468

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000256

AC:

285

AN:

1111998

Other (OTH)

AF:

0.000182

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000407

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5208

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000823

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000569

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.000422

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spermatogenic failure 11

Pathogenic:1Uncertain:1

Dec 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.16

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.067

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.82

M_CAP

Benign

0.0084

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.085

PhyloP100

1.4

PrimateAI

Uncertain

0.64

PROVEAN

Benign

3.2

REVEL

Uncertain

0.29

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.014

Vest4

0.71

MVP

0.87

MPC

0.59

ClinPred

0.050

GERP RS

6.2

Varity_R

0.13

gMVP

0.56

Mutation Taster

=28/72

disease causing

(source)

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over