X-151397330-G-A

Variant names:

• chrX-151397330-G-A
• rs1483109932
• NM_001017980.4:c.22G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017980.4(VMA21):​c.22G>A​(p.Ala8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,048,305 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: VMA21 NM_001017980.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.73
• Publications: 0 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)

ENSG00000287918 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08242965).

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.22G>A	p.Ala8Thr	missense	Exon 1 of 3	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.218+273G>A		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.22G>A	p.Ala8Thr	missense	Exon 1 of 3	ENSP00000333255.6	Q3ZAQ7-1
	VMA21	ENST00000932111.1		c.22G>A	p.Ala8Thr	missense	Exon 1 of 3	ENSP00000602170.1
	VMA21	ENST00000370361.5	TSL:5	c.218+273G>A		intron	N/A	ENSP00000359386.1	Q3ZAQ7-2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000987 AC: 1 AN: 101287 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000191 AC: 2 AN: 1048305 Hom.: 0 Cov.: 30 AF XY: 0.00000292 AC XY: 1 AN XY: 342401

African (AFR) AF: 0.00 AC: 0 AN: 24909

American (AMR) AF: 0.0000358 AC: 1 AN: 27938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18639

East Asian (EAS) AF: 0.0000369 AC: 1 AN: 27132

South Asian (SAS) AF: 0.00 AC: 0 AN: 49808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3987

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819282

Other (OTH) AF: 0.00 AC: 0 AN: 44292

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0033	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	N
PhyloP100		1.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.034
Sift	Benign	0.19	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.20		Loss of helix (P = 0.0123)
MVP		0.14
MPC		0.76
ClinPred		0.088	T
GERP RS		1.9
PromoterAI		0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.072
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1483109932; hg19: chrX-150565802;