rs587783772

Variant names:

• chrX-150659665-G-A
• rs587783772
• NM_000252.3:c.1262G>A
• MTM1 p.Arg421Gln

Your query was ambiguous. Multiple possible variants found:

• chrX-150659665-G-A
• chrX-150659665-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000252.3(MTM1):​c.1262G>A​(p.Arg421Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,092,415 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000634484: This variant has been reported to affect MTM1 protein function (PMID:23071445, 12646134, 23917616, 21135508, 17973976)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421L) has been classified as Likely pathogenic. The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MTM1 NM_000252.3 missense, splice_region
• Scores: Splicing: ADA: 0.9223
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.94
• Publications: 16 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000634484: This variant has been reported to affect MTM1 protein function (PMID: 23071445, 12646134, 23917616, 21135508, 17973976).; SCV000516968: Published functional studies demonstrate a damaging effect on phosphatase activity (PMID: 23071445, 17973976, 23917616, 12646134); SCV006040244: "In an assay testing MTM1 function, this variant showed a functionally abnormal result (Amoasii, 2012)."
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-150659665-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 599006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-150659665-G-A is Pathogenic according to our data. Variant chrX-150659665-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 158914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.1262G>A	p.Arg421Gln	missense splice_region	Exon 12 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1262G>A	p.Arg421Gln	missense splice_region	Exon 12 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1262G>A	p.Arg421Gln	missense splice_region	Exon 12 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.1262G>A	p.Arg421Gln	missense splice_region	Exon 12 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1307G>A	p.Arg436Gln	missense splice_region	Exon 13 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1307G>A	p.Arg436Gln	missense splice_region	Exon 13 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092415 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 358167

African (AFR) AF: 0.00 AC: 0 AN: 26299

American (AMR) AF: 0.00 AC: 0 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30151

South Asian (SAS) AF: 0.00 AC: 0 AN: 53982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 836915

Other (OTH) AF: 0.00 AC: 0 AN: 45898

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Severe X-linked myotubular myopathy (4)
2	-	-	not provided (2)
1	-	-	Centronuclear myopathy (1)
1	-	-	Congenital myopathy with fiber type disproportion (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.97
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.78
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

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

Other links and lift over

dbSNP: rs587783772;

hg19: chrX-149828138;

COSMIC: COSV60337210;