chr19-18565002-A-G

Variant names:

• chr19-18565002-A-G
• NM_024069.4:c.235A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024069.4(KXD1):​c.235A>G​(p.Ser79Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KXD1 NM_024069.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KXD1	NM_024069.4	c.235A>G	p.Ser79Gly	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	c.235A>G	p.Ser79Gly	missense_variant	Exon 3 of 5	1	NM_024069.4	ENSP00000222307.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.235A>G (p.S79G) alteration is located in exon 4 (coding exon 2) of the KXD1 gene. This alteration results from a A to G substitution at nucleotide position 235, causing the serine (S) at amino acid position 79 to be replaced by a glycine (G). 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	Benign	0.12
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;.;.;T;T;T;.;T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D;.;D;D;.;.;.;D;.;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.8	L;L;L;.;.;.;L;L;.;L;.;.
PhyloP100		6.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	D;D;D;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.29
Sift	Benign	0.34	T;T;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;D;.;.;.;D;D;.;D;.;.
Vest4		0.33
MutPred		0.47		Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);Loss of phosphorylation at S79 (P = 0.0649);
MVP		0.70
MPC		0.53
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.47
gMVP		0.83
Mutation Taster		=51/49	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

hg19: chr19-18675812;