X-151404934-A-G

Variant names:

• chrX-151404934-A-G
• rs141926826
• NM_001017980.4:c.182A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001017980.4(VMA21):​c.182A>G​(p.Asn61Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,208,466 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. N61N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 48 hem., cov: 22)
  • Exomes 𝑓: 0.00022 (0 hom. 54 hem.)
• Consequence: VMA21 NM_001017980.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.85
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008299381).
• BP6: Variant X-151404934-A-G is Benign according to our data. Variant chrX-151404934-A-G is described in ClinVar as Benign. ClinVar VariationId is 464819.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 48 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA21	NM_001017980.4	MANE Select	c.182A>G	p.Asn61Ser	missense	Exon 3 of 3	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.347A>G	p.Asn116Ser	missense	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.182A>G	p.Asn61Ser	missense	Exon 3 of 3	ENSP00000333255.6	Q3ZAQ7-1
	VMA21	ENST00000370361.5	TSL:5	c.347A>G	p.Asn116Ser	missense	Exon 4 of 4	ENSP00000359386.1	Q3ZAQ7-2
	VMA21	ENST00000932111.1		c.173A>G	p.Asn58Ser	missense	Exon 3 of 3	ENSP00000602170.1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 208 AN: 110477 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00614

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00193

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: 0.0000189

Gnomad OTH AF: 0.000675

GnomAD2 exomes AF: 0.000535 AC: 98 AN: 183159 AF XY: 0.000370

Gnomad AFR exome AF: 0.00654

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000216 AC: 237 AN: 1097937 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 54 AN XY: 363311

African (AFR) AF: 0.00557 AC: 147 AN: 26396

American (AMR) AF: 0.000483 AC: 17 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40417

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4134

European-Non Finnish (NFE) AF: 0.0000451 AC: 38 AN: 842011

Other (OTH) AF: 0.000694 AC: 32 AN: 46081

GnomAD4 genome AF: 0.00188 AC: 208 AN: 110529 Hom.: 0 Cov.: 22 AF XY: 0.00147 AC XY: 48 AN XY: 32737

African (AFR) AF: 0.00613 AC: 186 AN: 30339

American (AMR) AF: 0.00192 AC: 20 AN: 10393

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2539

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5865

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52850

Other (OTH) AF: 0.000667 AC: 1 AN: 1499

Alfa AF: 0.000677 Hom.: 36

Bravo AF: 0.00250

ESP6500AA AF: 0.00678 AC: 26

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000560 AC: 68

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	VMA21-related disorder (1)
-	-	1	X-linked myopathy with excessive autophagy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.79
DEOGEN2	Benign	0.0011	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N
PhyloP100		2.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.20	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.029
MVP		0.43
MPC		0.62
ClinPred		0.0073	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.57
Mutation Taster		=94/6	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: rs141926826; hg19: chrX-150573406; COSMIC: COSV57756246;