rs587783796

Positions:

• chrX-150598600-G-A
• chrX-150598600-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_000252.3(MTM1):​c.145G>A​(p.Val49Ile) variant causes a missense change. 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. V49F) has been classified as 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: 6.84

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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-150598600-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 158940.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant X-150598600-G-A is Pathogenic according to our data. Variant chrX-150598600-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158939.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.145G>A	p.Val49Ile	missense_variant	4/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.145G>A	p.Val49Ile	missense_variant	4/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.74	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.10	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.060	B;.
Vest4		0.58
MutPred		0.79		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.91
MPC		0.54
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.43
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: -8

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783796; hg19: chrX-149767064;