NM_001017980.4:c.272G>C

Variant names:

• chrX-151405024-G-C
• rs878854354
• NM_001017980.4:c.272G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001017980.4(VMA21):​c.272G>C​(p.Gly91Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: VMA21 NM_001017980.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.96
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-151405024-G-C is Pathogenic according to our data. Variant chrX-151405024-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208802.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA21	NM_001017980.4	MANE Select	c.272G>C	p.Gly91Ala	missense	Exon 3 of 3	NP_001017980.1
	VMA21	NM_001363810.1		c.437G>C	p.Gly146Ala	missense	Exon 3 of 3	NP_001350739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA21	ENST00000330374.7	TSL:1 MANE Select	c.272G>C	p.Gly91Ala	missense	Exon 3 of 3	ENSP00000333255.6
	VMA21	ENST00000370361.5	TSL:5	c.437G>C	p.Gly146Ala	missense	Exon 4 of 4	ENSP00000359386.1
	VMA21	ENST00000477649.1	TSL:3	n.352G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with excessive autophagy Pathogenic:2

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3+PM2+PP5

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	L
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.015	D
Polyphen		0.48	P
Vest4		0.68
MutPred		0.64		Loss of loop (P = 0.0022)
MVP		0.95
MPC		1.1
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.93
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs878854354; hg19: chrX-150573496;