X-151397331-C-T

Variant names:

• chrX-151397331-C-T
• rs1556034337
• NM_001017980.4:c.23C>T

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.23C>T​(p.Ala8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000954 in 1,048,138 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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. A8T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: VMA21 NM_001017980.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47
• 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=0.15848535).

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.23C>T	p.Ala8Val	missense	Exon 1 of 3	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.218+274C>T		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.23C>T	p.Ala8Val	missense	Exon 1 of 3	ENSP00000333255.6	Q3ZAQ7-1
	VMA21	ENST00000932111.1		c.23C>T	p.Ala8Val	missense	Exon 1 of 3	ENSP00000602170.1
	VMA21	ENST00000370361.5	TSL:5	c.218+274C>T		intron	N/A	ENSP00000359386.1	Q3ZAQ7-2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.54e-7 AC: 1 AN: 1048138 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 342230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24905

American (AMR) AF: 0.00 AC: 0 AN: 27928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18629

East Asian (EAS) AF: 0.00 AC: 0 AN: 27121

South Asian (SAS) AF: 0.00 AC: 0 AN: 49804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32331

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3986

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 819147

Other (OTH) AF: 0.00 AC: 0 AN: 44287

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0076	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.061
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.031	D
Polyphen		0.38	B
Vest4		0.22
MutPred		0.21		Loss of disorder (P = 0.0332)
MVP		0.20
MPC		0.78
ClinPred		0.74	D
GERP RS		4.3
PromoterAI		-0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.16
Mutation Taster		=81/19	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: rs1556034337; hg19: chrX-150565803;