X-151397319-C-T

Position:

• chrX-151397319-C-T

Variant summary

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

The NM_001017980.4(VMA21):​c.11C>T​(p.Pro4Leu) 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: VMA21 NM_001017980.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

Genes affected

VMA21 (HGNC:22082): (vacuolar ATPase assembly factor VMA21) This gene encodes a chaperone for assembly of lysosomal vacuolar ATPase.[provided by RefSeq, Jul 2012]

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=0.029080182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VMA21	NM_001017980.4	c.11C>T	p.Pro4Leu	missense_variant	1/3	ENST00000330374.7
VMA21	NM_001363810.1	c.218+262C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VMA21	ENST00000330374.7	c.11C>T	p.Pro4Leu	missense_variant	1/3	1	NM_001017980.4	P1
VMA21	ENST00000370361.5	c.218+262C>T		intron_variant		5
VMA21	ENST00000477649.1	n.133+672C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1047660 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 342074

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with excessive autophagy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the VMA21 protein (p.Pro4Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VMA21-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.6
DANN	Benign	0.89
DEOGEN2	Benign	0.0026	T
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.031
Sift	Benign	0.68	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.21		Loss of loop (P = 0.0031);
MVP		0.043
MPC		0.79
ClinPred		0.031	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029

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: chrX-150565791;