X-151397033-G-T

Variant names:

• chrX-151397033-G-T
• rs753376606
• NM_001363810.1:c.194G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001363810.1(VMA21):​c.194G>T​(p.Gly65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 389,199 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. 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. G65A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000023 (0 hom. 3 hem.)
• Consequence: VMA21 NM_001363810.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.984
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07777944).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001363810.1	c.194G>T	p.Gly65Val	missense_variant	Exon 1 of 3		NP_001350739.1
VMA21	NM_001017980.4	c.-276G>T		upstream_gene_variant		ENST00000330374.7	NP_001017980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VMA21	ENST00000330374.7	c.-276G>T		upstream_gene_variant		1	NM_001017980.4	ENSP00000333255.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.0000237 AC: 2 AN: 84537 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: 0.000153

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000322

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000231 AC: 9 AN: 389199 Hom.: 0 Cov.: 0 AF XY: 0.0000219 AC XY: 3 AN XY: 136977

African (AFR) AF: 0.00 AC: 0 AN: 11910

American (AMR) AF: 0.00 AC: 0 AN: 25802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14203

East Asian (EAS) AF: 0.000340 AC: 8 AN: 23526

South Asian (SAS) AF: 0.00 AC: 0 AN: 36515

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2120

European-Non Finnish (NFE) AF: 0.00000446 AC: 1 AN: 224285

Other (OTH) AF: 0.00 AC: 0 AN: 22272

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	2.2
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.98
PROVEAN	Benign	0.070	N
REVEL	Benign	0.0010
Sift	Uncertain	0.011	D
Sift4G	Benign	0.19	T
Vest4		0.073
MutPred		0.26		Gain of sheet (P = 0.0016);
MVP		0.35
ClinPred		0.022	T
GERP RS		-0.93
PromoterAI		0.13	Neutral
gMVP		0.49
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs753376606; hg19: chrX-150565505;