rs587783823

Variant names:

• chrX-150592617-G-A
• rs587783823
• NM_000252.3:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000252.3(MTM1):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MTM1 NM_000252.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.53
• Publications: 0 publications found

Genes affected

MTM1 (HGNC:7448): (myotubularin 1) This gene encodes a dual-specificity phosphatase that acts on both phosphotyrosine and phosphoserine. It is required for muscle cell differentiation and mutations in this gene have been identified as being responsible for X-linked myotubular myopathy. [provided by RefSeq, Jul 2008]

MTM1 Gene-Disease associations (from GenCC):

• X-linked myotubular myopathy

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 34 pathogenic variants. Next in-frame start position is after 96 codons. Genomic position: 150614643. Lost 0.158 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150592617-G-A is Pathogenic according to our data. Variant chrX-150592617-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 158969.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000252.3. 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
	MTM1	NM_000252.3	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 15	NP_000243.1
	MTM1	NM_001376908.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 15	NP_001363837.1
	MTM1	NM_001376906.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 15	NP_001363835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 15	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 16	ENSP00000510607.1
	MTM1	ENST00000866458.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1083248 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 350392

African (AFR) AF: 0.00 AC: 0 AN: 26148

American (AMR) AF: 0.00 AC: 0 AN: 35168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19295

East Asian (EAS) AF: 0.00 AC: 0 AN: 30120

South Asian (SAS) AF: 0.00 AC: 0 AN: 53825

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40107

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828889

Other (OTH) AF: 0.00 AC: 0 AN: 45602

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.68
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.49	D
PhyloP100		6.5
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.021	D
Sift4G	Benign	0.50	T
Polyphen		0.036	B
Vest4		0.90
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0633)
MVP		1.0
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.57
gMVP		0.83
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs587783823; hg19: chrX-149761079;