rs878854355

chrX-151405064-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

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 Pathogenic (★).

• 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

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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 ClinVar as [Pathogenic]. Clinvar id is 208803.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-151405064-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VMA21	NM_001017980.4	c.*6A>G		3_prime_UTR_variant	3/3	ENST00000330374.7
VMA21	NM_001363810.1	c.*6A>G		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VMA21	ENST00000330374.7	c.*6A>G		3_prime_UTR_variant	3/3	1	NM_001017980.4	P1
VMA21	ENST00000370361.5	c.*6A>G		3_prime_UTR_variant	4/4	5
VMA21	ENST00000477649.1	n.392A>G		non_coding_transcript_exon_variant	3/3	3

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 08, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 208803). This variant has been observed in individuals with X-linked myopathy with excessive autophagy (XMEA) (PMID: 23315026). This variant is not present in population databases (gnomAD no frequency). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Uncertain	24
Dann	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854355; hg19: chrX-150573536;