19-18567134-C-G

Variant names:

• chr19-18567134-C-G
• rs778930671
• NM_024069.4:c.257C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024069.4(KXD1):​c.257C>G​(p.Thr86Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T86M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: KXD1 NM_024069.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42
• Publications: 0 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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24098903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KXD1	NM_024069.4	c.257C>G	p.Thr86Arg	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000222307.9	NP_076974.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KXD1	ENST00000222307.9	c.257C>G	p.Thr86Arg	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_024069.4	ENSP00000222307.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250632 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.016	T;T;T;.;.;T;T;T;.;T;T;T
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;D;T;.;.;.;D;.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.5	L;L;L;.;.;.;L;L;.;L;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N;N;N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.22	T;T;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.18	T;T;T;T;D;T;T;T;T;T;T;T
Polyphen		0.97	D;D;D;.;.;.;D;D;.;D;.;.
Vest4		0.72
MutPred		0.48		Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);.;Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);Loss of phosphorylation at T86 (P = 0.0099);
MVP		0.67
MPC		0.76
ClinPred		0.24	T
GERP RS		2.6
Varity_R		0.23
gMVP		0.87
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778930671; hg19: chr19-18677944;