19-18565015-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_024069.4(KXD1):c.248G>A(p.Arg83His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,596,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

KXD1
NM_024069.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.66

Publications

4 publications found

Variant links:

Genes affected

KXD1 (HGNC:28420): (KxDL motif containing 1) Involved in lysosome localization. Part of BORC complex. [provided by Alliance of Genome Resources, Apr 2022]

KXD1 links:

UBA52 (HGNC:12458): (ubiquitin A-52 residue ribosomal protein fusion product 1) Ubiquitin is a highly conserved nuclear and cytoplasmic protein that has a major role in targeting cellular proteins for degradation by the 26S proteosome. It is also involved in the maintenance of chromatin structure, the regulation of gene expression, and the stress response. Ubiquitin is synthesized as a precursor protein consisting of either polyubiquitin chains or a single ubiquitin moiety fused to an unrelated protein. This gene encodes a fusion protein consisting of ubiquitin at the N terminus and ribosomal protein L40 at the C terminus, a C-terminal extension protein (CEP). Multiple processed pseudogenes derived from this gene are present in the genome. [provided by RefSeq, Jul 2008]

UBA52 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KXD1	NM_024069.4 link	c.248G>A	p.Arg83His	missense_variant	Exon 3 of 5	ENST00000222307.9	NP_076974.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KXD1	ENST00000222307.9 link	c.248G>A	p.Arg83His	missense_variant	Exon 3 of 5	1	NM_024069.4	ENSP00000222307.3		Q9BQD3

Frequencies

GnomAD3 genomes

AF:

0.000214

AC:

AN:

144730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000204

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000360

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

239862

AF XY:

0.000161

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000748

Gnomad NFE exome

AF:

0.000305

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000294

AC:

427

AN:

1451860

Hom.:

Cov.:

AF XY:

0.000304

AC XY:

220

AN XY:

722536

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000458

AC:

AN:

43634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000337

AC:

375

AN:

1111848

Other (OTH)

AF:

0.000796

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000214

AC:

AN:

144730

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

AN XY:

70284

show subpopulations

African (AFR)

AF:

0.000132

AC:

AN:

37930

American (AMR)

AF:

0.00

AC:

AN:

14194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.000204

AC:

AN:

4900

South Asian (SAS)

AF:

0.00

AC:

AN:

4576

European-Finnish (FIN)

AF:

0.000101

AC:

AN:

9916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.000360

AC:

AN:

66602

Other (OTH)

AF:

0.00

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000297

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000655

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.248G>A (p.R83H) alteration is located in exon 4 (coding exon 2) of the KXD1 gene. This alteration results from a G to A substitution at nucleotide position 248, causing the arginine (R) at amino acid position 83 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

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;T;T;.;.;T;T;T;.;T;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;.;D;D;.;.;.;D;.;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.5

M;M;M;.;.;.;M;M;.;M;.;.

PhyloP100

8.7

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.3

D;D;D;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.0030

D;D;D;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.0070

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;.;.;D;D;.;D;.;.

Vest4

0.88

MVP

0.80

MPC

1.7

ClinPred

0.84

GERP RS

5.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.93

gMVP

0.90

Mutation Taster

=33/67

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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19-18565015-G-A

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