Genetic Variant MTM1:p.Arg421Leu (chrX-150659665-G-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000252.3(MTM1):c.1262G>T(p.Arg421Leu) variant causes a missense, splice region 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. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

MTM1
NM_000252.3 missense, splice_region

Scores

Splicing: ADA: 0.9250

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.94

Publications

16 publications found

Variant links:

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, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, G2P, Orphanet

MTM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

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-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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant X-150659665-G-T is Pathogenic according to our data. 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	NM_000252.3	MANE Select	c.1262G>T	p.Arg421Leu	missense splice_region	Exon 12 of 15	NP_000243.1	Q13496-1
MTM1	NM_001376908.1		c.1262G>T	p.Arg421Leu	missense splice_region	Exon 12 of 15	NP_001363837.1	Q13496-1
MTM1	NM_001376906.1		c.1262G>T	p.Arg421Leu	missense splice_region	Exon 12 of 15	NP_001363835.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	ENST00000370396.7	TSL:1 MANE Select	c.1262G>T	p.Arg421Leu	missense splice_region	Exon 12 of 15	ENSP00000359423.3	Q13496-1
MTM1	ENST00000689314.1		c.1307G>T	p.Arg436Leu	missense splice_region	Exon 13 of 16	ENSP00000510607.1	A0A8I5KZ76
MTM1	ENST00000866458.1		c.1307G>T	p.Arg436Leu	missense splice_region	Exon 13 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.83

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

PhyloP100

9.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.91

Loss of disorder (P = 0.0306)

MVP

1.0

MPC

1.8

ClinPred

1.0

GERP RS

5.4

Varity_R

0.98

gMVP

0.99

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.80

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over