rs1412988171

Variant names:

• chrX-151397349-C-T
• rs1412988171
• NM_001017980.4:c.41C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001017980.4(VMA21):​c.41C>T​(p.Pro14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,161,719 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 (★). Synonymous variant affecting the same amino acid position (i.e. P14P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: VMA21 NM_001017980.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.122
• 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: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000287918 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058118433).
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

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.41C>T	p.Pro14Leu	missense	Exon 1 of 3	NP_001017980.1
	VMA21	NM_001363810.1		c.218+292C>T		intron	N/A	NP_001350739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA21	ENST00000330374.7	TSL:1 MANE Select	c.41C>T	p.Pro14Leu	missense	Exon 1 of 3	ENSP00000333255.6
	VMA21	ENST00000370361.5	TSL:5	c.218+292C>T		intron	N/A	ENSP00000359386.1
	VMA21	ENST00000477649.1	TSL:3	n.133+702C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000882 AC: 1 AN: 113349 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.000652

GnomAD2 exomes AF: 0.00 AC: 0 AN: 101866 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000162 AC: 17 AN: 1048370 Hom.: 0 Cov.: 30 AF XY: 0.0000175 AC XY: 6 AN XY: 342380

African (AFR) AF: 0.00 AC: 0 AN: 24906

American (AMR) AF: 0.00 AC: 0 AN: 27926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18644

East Asian (EAS) AF: 0.00 AC: 0 AN: 27125

South Asian (SAS) AF: 0.00 AC: 0 AN: 49820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.0000195 AC: 16 AN: 819227

Other (OTH) AF: 0.0000226 AC: 1 AN: 44302

GnomAD4 genome AF: 0.00000882 AC: 1 AN: 113349 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 35477

African (AFR) AF: 0.00 AC: 0 AN: 31283

American (AMR) AF: 0.00 AC: 0 AN: 10879

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53358

Other (OTH) AF: 0.000652 AC: 1 AN: 1533

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

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	0.096
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.9
DANN	Benign	0.93
DEOGEN2	Benign	0.0070	T
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.12
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.020
Sift	Benign	0.066	T
Sift4G	Benign	0.067	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.043
MPC		0.79
ClinPred		0.15	T
GERP RS		2.4
PromoterAI		0.041	Neutral
Varity_R		0.050
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: rs1412988171; hg19: chrX-150565821;