rs878854355

Variant names:

• chrX-151405064-A-G
• rs878854355
• NM_001017980.4:c.*6A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001017980.4(VMA21):​c.*6A>G variant causes a 3 prime UTR 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: VMA21 NM_001017980.4 3_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.439
• Publications: 2 publications found

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]

VMA21 Gene-Disease associations (from GenCC):

• X-linked myopathy with excessive autophagy

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-151405064-A-G is Pathogenic according to our data. Variant chrX-151405064-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 208803.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001017980.4	c.*6A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1	c.*6A>G		3_prime_UTR_variant	Exon 3 of 3		NP_001350739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VMA21	ENST00000330374.7	c.*6A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_001017980.4	ENSP00000333255.6
VMA21	ENST00000477649.1	n.392A>G		non_coding_transcript_exon_variant	Exon 3 of 3	3
VMA21	ENST00000370361.5	c.*6A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000359386.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with excessive autophagy Pathogenic:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the VMA21 gene. It does not change the encoded amino acid sequence of the VMA21 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with X-linked myopathy with excessive autophagy (XMEA) (PMID: 23315026). ClinVar contains an entry for this variant (Variation ID: 208803). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VMA21 function (PMID: 23315026). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Uncertain	24
DANN	Benign	0.56
PhyloP100		0.44
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: -5

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

Other links and lift over

dbSNP: rs878854355; hg19: chrX-150573536;