19-18568618-T-C

Variant names:

• chr19-18568618-T-C
• rs2145266338
• NM_024069.4:c.518T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024069.4(KXD1):​c.518T>C​(p.Met173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. M173R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KXD1 NM_024069.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.49
• 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]

KXD1-AS1 (HGNC:56662): (KXD1 antisense RNA 1)

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031069726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KXD1	NM_024069.4	c.518T>C	p.Met173Thr	missense_variant	Exon 5 of 5	ENST00000222307.9	NP_076974.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KXD1	ENST00000222307.9	c.518T>C	p.Met173Thr	missense_variant	Exon 5 of 5	1	NM_024069.4	ENSP00000222307.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.032
DANN	Benign	0.32
DEOGEN2	Benign	0.0063	T;T;T;.;T;T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.23	.;T;.;T;.;.;.
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.031	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;N;N;.;N;N;N
PhyloP100		-3.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.36	N;N;N;.;.;.;.
REVEL	Benign	0.035
Sift	Benign	1.0	T;T;T;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;B
Vest4		0.059
MutPred		0.17		Gain of phosphorylation at M173 (P = 0.0165);Gain of phosphorylation at M173 (P = 0.0165);Gain of phosphorylation at M173 (P = 0.0165);.;Gain of phosphorylation at M173 (P = 0.0165);Gain of phosphorylation at M173 (P = 0.0165);Gain of phosphorylation at M173 (P = 0.0165);
MVP		0.048
MPC		0.63
ClinPred		0.021	T
GERP RS		-10
Varity_R		0.016
gMVP		0.034
Mutation Taster		=100/0	polymorphism

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: rs2145266338; hg19: chr19-18679428;