chrX-151403744-A-G

Position:

• chrX-151403744-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001017980.4(VMA21):​c.163+4A>G variant causes a splice donor region, intron change. 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: 24)
• Consequence: VMA21 NM_001017980.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9592
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.07

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• PP5: Variant X-151403744-A-G is Pathogenic according to our data. Variant chrX-151403744-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-151403744-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VMA21	NM_001017980.4	c.163+4A>G		splice_donor_region_variant, intron_variant		ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1	c.328+4A>G		splice_donor_region_variant, intron_variant			NP_001350739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VMA21	ENST00000330374.7	c.163+4A>G		splice_donor_region_variant, intron_variant		1	NM_001017980.4	ENSP00000333255	P1
VMA21	ENST00000370361.5	c.328+4A>G		splice_donor_region_variant, intron_variant		5		ENSP00000359386
VMA21	ENST00000477649.1	n.243+4A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked myopathy with excessive autophagy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects 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: 208720). This variant has been observed in individuals with X-linked myopathy with excessive autophagy (PMID: 23315026, 25809233). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the VMA21 gene. It does not directly change the encoded amino acid sequence of the VMA21 protein. It affects a nucleotide within the consensus splice site. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2014

The c.163+4A>G intronic alteration consists of a A to G substitution nucleotides after coding exon 2 in the VMA21 gene. The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the c.163+4A>G alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). REFERENCES: Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered nucleotide is conserved throughout evolution:_x000D_ _x000D_ This nucleotide position is highly conserved in available vertebrate species. Functional analysis reveals a damaging effect of the nucleotide alteration: _x000D_ _x000D_ (Ramachandran, 2013): "c.163+4A>G, removes the A in the +4 position after exon 2, which contributes to optimal U1 snRNA binding during splicing." Demonstration of RNA reduction by quantative RT-PCR and protein level reduction by Western (in vitro analyses included both pateint fibroblast and lymphoblasts as well as yeast complementation assay) The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The c.163+4A>G alteration is predicted to weaken the native splice donor site efficiency by the in silico programs Fruitfly and ESEfinder 3.0. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.65		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044909; hg19: chrX-150572216;