rs878854353

Positions:

• chrX-151404909-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001017980.4(VMA21):​c.164-7T>G variant causes a splice region, splice polypyrimidine tract, intron 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: VMA21 NM_001017980.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003363
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.32

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-151404909-T-G is Pathogenic according to our data. Variant chrX-151404909-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 208801.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-151404909-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VMA21	NM_001017980.4	c.164-7T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1	c.329-7T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001350739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VMA21	ENST00000330374.7	c.164-7T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001017980.4	ENSP00000333255	P1
VMA21	ENST00000370361.5	c.329-7T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000359386
VMA21	ENST00000477649.1	n.244-7T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with excessive autophagy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 13, 2019	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect VMA21 protein function (PMID: 23315026). This variant has been observed in several individuals affected with X-linked myopathy with excessive autophagy (PMID: 23315026, 23850239, 24488655). ClinVar contains an entry for this variant (Variation ID: 208801). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0034
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854353; hg19: chrX-150573381;