chrX-151403744-A-G

Variant names:

• chrX-151403744-A-G
• rs797044909
• NM_001017980.4:c.163+4A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_001017980.4(VMA21):​c.163+4A>G variant causes a splice region, intron change. 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000244178: Functional analysis reveals a damaging effect of the nucleotide alteration: "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: (Ramachandran, 2013)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: VMA21 NM_001017980.4 splice_region, intron
• Scores: Splicing: ADA: 0.9592
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.07
• Publications: 3 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000244178: Functional analysis reveals a damaging effect of the nucleotide alteration: "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: (Ramachandran, 2013); SCV000821307: Experimental studies have shown that this variant affects VMA21 function (PMID: 23315026).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 208720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017980.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA21	NM_001017980.4	MANE Select	c.163+4A>G		splice_region intron	N/A	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.328+4A>G		splice_region intron	N/A	NP_001350739.1	Q3ZAQ7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA21	ENST00000330374.7	TSL:1 MANE Select	c.163+4A>G		splice_region intron	N/A	ENSP00000333255.6	Q3ZAQ7-1
	VMA21	ENST00000370361.5	TSL:5	c.328+4A>G		splice_region intron	N/A	ENSP00000359386.1	Q3ZAQ7-2
	VMA21	ENST00000932111.1		c.154+4A>G		splice_region intron	N/A	ENSP00000602170.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	X-linked myopathy with excessive autophagy (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.93
PhyloP100		5.1
Mutation Taster		=33/67	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044909; hg19: chrX-150572216;