X-151397319-C-A

Variant names:

• chrX-151397319-C-A
• rs1465930949
• NM_001017980.4:c.11C>A

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>A​(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,047,658 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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 (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• 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=0.038425148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001017980.4	c.11C>A	p.Pro4Gln	missense_variant	Exon 1 of 3	ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1	c.218+262C>A		intron_variant	Intron 1 of 2		NP_001350739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VMA21	ENST00000330374.7	c.11C>A	p.Pro4Gln	missense_variant	Exon 1 of 3	1	NM_001017980.4	ENSP00000333255.6
VMA21	ENST00000370361.5	c.218+262C>A		intron_variant	Intron 2 of 3	5		ENSP00000359386.1
VMA21	ENST00000477649.1	n.133+672C>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000191 AC: 2 AN: 1047658 Hom.: 0 Cov.: 30 AF XY: 0.00000292 AC XY: 1 AN XY: 342076

Gnomad4 AFR exome AF: 0.0000803

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

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with excessive autophagy Uncertain:1

Sep 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with VMA21-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 4 of the VMA21 protein (p.Pro4Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.74
DEOGEN2	Benign	0.0011	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.042
Sift	Benign	0.29	T
Sift4G	Benign	0.43	T
Polyphen		0.031	B
Vest4		0.15
MutPred		0.16		Loss of loop (P = 0.0031);
MVP		0.068
MPC		0.76
ClinPred		0.063	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041

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

LitVar

Other links and lift over

dbSNP: rs1465930949; hg19: chrX-150565791;