chrX-150659694-G-A

Variant names:

• chrX-150659694-G-A
• rs886044782
• NM_000252.3:c.1291G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000252.3(MTM1):​c.1291G>A​(p.Asp431Asn) 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).

• 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:3
• Conservation: PhyloP100: 9.94
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant X-150659694-G-A is Pathogenic according to our data. Variant chrX-150659694-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281932.

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.1291G>A	p.Asp431Asn	missense	Exon 12 of 15	NP_000243.1
	MTM1	NM_001376908.1		c.1291G>A	p.Asp431Asn	missense	Exon 12 of 15	NP_001363837.1
	MTM1	NM_001376906.1		c.1291G>A	p.Asp431Asn	missense	Exon 12 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.1291G>A	p.Asp431Asn	missense	Exon 12 of 15	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.1336G>A	p.Asp446Asn	missense	Exon 13 of 16	ENSP00000510607.1
	MTM1	ENST00000685944.1		c.1291G>A	p.Asp431Asn	missense	Exon 12 of 15	ENSP00000509266.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

May 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp431Asn variant in MTM1 has been reported in 1 male with X-linked recessive myotubular myopathy, who carried a second variant 2 amino acids downstream on the same allele (p.Asp433Asn; Laporte 1997). Please note, it is unclear if these two variants occurred independently or as a single event (p.Asp431_Asp433delinsAsnAlaAsn). Both variants were absent from large population studies. Computational prediction tools and conservation analyses suggest that the p.Asp431Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp431Asn variant is uncertain.

May 16, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 29, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The D431N variant in the MTM1 gene has been reported in a male patient affected with X-linked myotubular myopathy whose mother was noted to be a carrier (Laporte et al., 1997). The D431N variant was reported in cis with a second D433N variant, however the two missense variants are nearby and therefore would be considered as an insertion deletion alteration c.1291_1297delGATGCTGinsAATGCTA using alternate nomenclature. The D431N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D431N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (R421Q) has been reported in the Human Gene Mutation Database in association with X-linked recessive myotubular myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The D431N variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded

not specified Uncertain:1

May 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.5	L
PhyloP100		9.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.48
Sift	Benign	0.036	D
Sift4G	Benign	0.062	T
Polyphen		0.58	P
Vest4		0.82
MutPred		0.25		Loss of ubiquitination at K427 (P = 0.0828)
MVP		0.96
MPC		1.6
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.56
gMVP		0.80
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -30

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

Other links and lift over

dbSNP: rs886044782; hg19: chrX-149828167; COSMIC: COSV100080294;