X-151404918-G-T

Variant names:

• chrX-151404918-G-T
• rs140025330
• NM_001017980.4:c.166G>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.166G>T​(p.Ala56Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000927 in 107,839 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. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000093 (0 hom., 0 hem., cov: 22)
• Consequence: VMA21 NM_001017980.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 2 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: 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=0.11200678).

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.166G>T	p.Ala56Ser	missense splice_region	Exon 3 of 3	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.331G>T	p.Ala111Ser	missense splice_region	Exon 3 of 3	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.166G>T	p.Ala56Ser	missense splice_region	Exon 3 of 3	ENSP00000333255.6	Q3ZAQ7-1
	VMA21	ENST00000370361.5	TSL:5	c.331G>T	p.Ala111Ser	missense splice_region	Exon 4 of 4	ENSP00000359386.1	Q3ZAQ7-2
	VMA21	ENST00000932111.1		c.157G>T	p.Ala53Ser	missense splice_region	Exon 3 of 3	ENSP00000602170.1

Frequencies

GnomAD3 genomes AF: 0.00000927 AC: 1 AN: 107839 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000927 AC: 1 AN: 107839 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 30561

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

African (AFR) AF: 0.0000341 AC: 1 AN: 29366

American (AMR) AF: 0.00 AC: 0 AN: 10014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2607

East Asian (EAS) AF: 0.00 AC: 0 AN: 3463

South Asian (SAS) AF: 0.00 AC: 0 AN: 2440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5269

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52322

Other (OTH) AF: 0.00 AC: 0 AN: 1446

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0017	T
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.42	N
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.058
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.042	B
Vest4		0.13
MutPred		0.51		Gain of sheet (P = 0.0028)
MVP		0.38
MPC		0.72
ClinPred		0.36	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.76
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs140025330; hg19: chrX-150573390;