chrX-151403604-A-C

Variant names:

• chrX-151403604-A-C
• rs878854352
• NM_001017980.4:c.54-27A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017980.4(VMA21):​c.54-27A>C variant causes a 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. Variant has been reported in ClinVar as Uncertain significance (★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 24)
• Consequence: VMA21 NM_001017980.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.453

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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001017980.4	c.54-27A>C		intron_variant	Intron 1 of 2	ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1	c.219-27A>C		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.54-27A>C		intron_variant	Intron 1 of 2	1	NM_001017980.4	ENSP00000333255.6
VMA21	ENST00000370361.5	c.219-27A>C		intron_variant	Intron 2 of 3	5		ENSP00000359386.1
VMA21	ENST00000477649.1	n.134-27A>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with excessive autophagy Pathogenic:1 Uncertain:1

Jul 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with X-linked myopathy with excessive autophagy (PMID: 23315026). ClinVar contains an entry for this variant (Variation ID: 208798). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 1 of the VMA21 gene. It does not directly change the encoded amino acid sequence of the VMA21 protein. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VMA21 protein function (PMID: 23315026). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. -

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	-0.68
CADD	Benign	0.027
DANN	Benign	0.75
La Branchor		0.94
BranchPoint Hunter		7.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.74		Position offset: 27

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854352; hg19: chrX-150572076;