19-18568618-T-G

Position:

• chr19-18568618-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024069.4(KXD1):​c.518T>G​(p.Met173Arg) 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. 15/21 in silico tools predict a benign outcome for this variant. 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: -3.49

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050219834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KXD1	NM_024069.4	c.518T>G	p.Met173Arg	missense_variant	5/5	ENST00000222307.9	NP_076974.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KXD1	ENST00000222307.9	c.518T>G	p.Met173Arg	missense_variant	5/5	1	NM_024069.4	ENSP00000222307	P1
KXD1-AS1	ENST00000593791.1	n.320A>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.518T>G (p.M173R) alteration is located in exon 6 (coding exon 4) of the KXD1 gene. This alteration results from a T to G substitution at nucleotide position 518, causing the methionine (M) at amino acid position 173 to be replaced by an arginine (R). 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	0.059
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.032
DANN	Benign	0.40
DEOGEN2	Benign	0.0055	T;T;T;.;T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.30	.;T;.;T;.;.;.
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.050	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;.;L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.25	N;N;N;.;.;.;.
REVEL	Benign	0.043
Sift	Benign	0.13	T;T;T;.;.;.;.
Sift4G	Benign	0.43	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;B
Vest4		0.12
MutPred		0.18		Loss of glycosylation at T174 (P = 0.0518);Loss of glycosylation at T174 (P = 0.0518);Loss of glycosylation at T174 (P = 0.0518);.;Loss of glycosylation at T174 (P = 0.0518);Loss of glycosylation at T174 (P = 0.0518);Loss of glycosylation at T174 (P = 0.0518);
MVP		0.055
MPC		0.83
ClinPred		0.079	T
GERP RS		-10
Varity_R		0.15
gMVP		0.043

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18679428;