MTM1 p.Ile412Leu

Variant names:

• chrX-150658001-A-T
• NM_000252.3:c.1234A>T
• MTM1 p.Ile412Leu

Your query was ambiguous. Multiple possible variants found:

• chrX-150658001-A-T
• chrX-150658001-A-C
• chrX-150658001-ATA-TTG
• chrX-150658001-ATA-CTT
• chrX-150658001-ATA-CTC
• chrX-150658001-ATA-CTG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000252.3(MTM1):​c.1234A>T​(p.Ile412Leu) 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. 14/23 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I412V) has been classified as Likely pathogenic. The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• 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: ClinGen, G2P, Orphanet, Genomics England PanelApp, Myriad Women's Health, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Specifications for MTM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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-150658001-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158907.

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.1234A>T	p.Ile412Leu	missense	Exon 11 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1234A>T	p.Ile412Leu	missense	Exon 11 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1234A>T	p.Ile412Leu	missense	Exon 11 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.1234A>T	p.Ile412Leu	missense	Exon 11 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1279A>T	p.Ile427Leu	missense	Exon 12 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1279A>T	p.Ile427Leu	missense	Exon 12 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.62
DEOGEN2	Uncertain	0.56	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.030	N
PhyloP100		1.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.85	T
Varity_R		0.35
gMVP		0.79
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -16

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-149826474;