chrX-151397319-C-T

Variant names:

• chrX-151397319-C-T
• rs1465930949
• NM_001017980.4:c.11C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001017980.4(VMA21):​c.11C>T​(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: VMA21 NM_001017980.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.11
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029080182).
• BP6: Variant X-151397319-C-T is Benign according to our data. Variant chrX-151397319-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2805853.

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.11C>T	p.Pro4Leu	missense	Exon 1 of 3	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.218+262C>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.11C>T	p.Pro4Leu	missense	Exon 1 of 3	ENSP00000333255.6	Q3ZAQ7-1
	VMA21	ENST00000932111.1		c.11C>T	p.Pro4Leu	missense	Exon 1 of 3	ENSP00000602170.1
	VMA21	ENST00000370361.5	TSL:5	c.218+262C>T		intron	N/A	ENSP00000359386.1	Q3ZAQ7-2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1047660 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 342074

African (AFR) AF: 0.00 AC: 0 AN: 24892

American (AMR) AF: 0.00 AC: 0 AN: 27919

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18632

East Asian (EAS) AF: 0.00 AC: 0 AN: 27114

South Asian (SAS) AF: 0.00 AC: 0 AN: 49775

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31977

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3941

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819137

Other (OTH) AF: 0.00 AC: 0 AN: 44273

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	0.050
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.6
DANN	Benign	0.89
DEOGEN2	Benign	0.0026	T
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.031
Sift	Benign	0.68	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.21		Loss of loop (P = 0.0031)
MVP		0.043
MPC		0.79
ClinPred		0.031	T
GERP RS		4.0
PromoterAI		-0.099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
Mutation Taster		=89/11	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: rs1465930949; hg19: chrX-150565791;