X-150660423-A-G

Variant names:

• chrX-150660423-A-G
• rs587783789
• NM_000252.3:c.1406A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000252.3(MTM1):​c.1406A>G​(p.His469Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H469D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.90
• Publications: 2 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-150660422-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2150084.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-150660423-A-G is Pathogenic according to our data. Variant chrX-150660423-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158932.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.1406A>G	p.His469Arg	missense	Exon 13 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1406A>G	p.His469Arg	missense	Exon 13 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1406A>G	p.His469Arg	missense	Exon 13 of 15	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.1406A>G	p.His469Arg	missense	Exon 13 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1451A>G	p.His484Arg	missense	Exon 14 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1451A>G	p.His484Arg	missense	Exon 14 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Severe X-linked myotubular myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.91
MutPred		0.91		Gain of catalytic residue at H469 (P = 0.1683)
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs587783789; hg19: chrX-149828896;