14-50112616-G-A

Position:

• chr14-50112616-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024558.3(VCPKMT):​c.674C>T​(p.Ser225Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,368,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: VCPKMT NM_024558.3 missense, splice_region
• Scores: Splicing: ADA: 0.005386
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.513

Genes affected

VCPKMT (HGNC:20352): (valosin containing protein lysine methyltransferase) Enables ATPase binding activity and protein-lysine N-methyltransferase activity. Involved in negative regulation of ATPase activity and peptidyl-lysine trimethylation. Located in cytosol. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07369238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCPKMT	NM_024558.3	c.674C>T	p.Ser225Leu	missense_variant, splice_region_variant	5/6	ENST00000395860.7	NP_078834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCPKMT	ENST00000395860.7	c.674C>T	p.Ser225Leu	missense_variant, splice_region_variant	5/6	1	NM_024558.3	ENSP00000379201	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000197 AC: 27 AN: 1368802 Hom.: 0 Cov.: 24 AF XY: 0.0000206 AC XY: 14 AN XY: 678686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.0000406

Gnomad4 NFE exome AF: 0.0000229

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000388 Hom.: 0

ExAC AF: 0.0000173 AC: 2

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

Apr 04, 2024

The c.674C>T (p.S225L) alteration is located in exon 5 (coding exon 5) of the VCPKMT gene. This alteration results from a C to T substitution at nucleotide position 674, causing the serine (S) at amino acid position 225 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	Benign	0.097
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.029
Sift	Benign	0.046	D
Sift4G	Benign	0.32	T
Polyphen		0.015	B
Vest4		0.23
MVP		0.27
MPC		0.0067
ClinPred		0.079	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0054
dbscSNV1_RF	Benign	0.098
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750264926; hg19: chr14-50579334; COSMIC: COSV53566900; COSMIC: COSV53566900;