chr19-18562097-G-T

Variant names:

• chr19-18562097-G-T
• rs772575509
• NM_024069.4:c.41G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024069.4(KXD1):​c.41G>T​(p.Arg14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,612,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KXD1 NM_024069.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64
• Publications: 1 publications found

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4192091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KXD1	NM_024069.4	c.41G>T	p.Arg14Leu	missense_variant	Exon 2 of 5	ENST00000222307.9	NP_076974.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KXD1	ENST00000222307.9	c.41G>T	p.Arg14Leu	missense_variant	Exon 2 of 5	1	NM_024069.4	ENSP00000222307.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

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

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249262 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000274

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460768 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726614

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111506

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41G>T (p.R14L) alteration is located in exon 3 (coding exon 1) of the KXD1 gene. This alteration results from a G to T substitution at nucleotide position 41, causing the arginine (R) at amino acid position 14 to be replaced by a leucine (L). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;.;.;T;T;.;T;.;T;T;T
Eigen	Benign	0.087
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	.;D;.;D;D;.;.;D;.;D;.;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L;L;L;.;.;.;L;.;L;.;L;.;.
PhyloP100		4.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D;D;D;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.16	T;T;T;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.045	B;B;B;.;.;.;B;.;B;.;B;.;.
Vest4		0.79
MutPred		0.64		Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);Loss of loop (P = 0.2897);
MVP		0.49
MPC		0.73
ClinPred		0.41	T
GERP RS		5.4
PromoterAI		0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.95
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs772575509; hg19: chr19-18672907;