rs587783785

chrX-150660393-A-GchrX-150660393-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP6 BS1 BS2

The NM_000252.3(MTM1):c.1376A>G(p.Asn459Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,194,034 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 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. N459I) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000018 (0 hom. 5 hem.)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 8.90

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_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000252.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-150660393-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 158927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant X-150660393-A-G is Benign according to our data. Variant chrX-150660393-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 744143.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000185 (20/1081818) while in subpopulation EAS AF= 0.000166 (5/30125). AF 95% confidence interval is 0.0000648. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.1376A>G	p.Asn459Ser	missense_variant	13/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.1376A>G	p.Asn459Ser	missense_variant	13/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112166 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34344

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000548 AC: 10 AN: 182415 Hom.: 0 AF XY: 0.0000596 AC XY: 4 AN XY: 67081

Gnomad AFR exome AF: 0.0000763

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000361

Gnomad SAS exome AF: 0.000158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000185 AC: 20 AN: 1081818 Hom.: 0 Cov.: 27 AF XY: 0.0000143 AC XY: 5 AN XY: 349724

Gnomad4 AFR exome AF: 0.0000383

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112216 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34404

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000279

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe X-linked myotubular myopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.1376A>G (p.N459S) alteration is located in exon 13 (coding exon 12) of the MTM1 gene. This alteration results from a A to G substitution at nucleotide position 1376, causing the asparagine (N) at amino acid position 459 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.074	T
Polyphen		0.66	P
Vest4		0.36
MutPred		0.78		Gain of disorder (P = 0.2072);
MVP		0.98
MPC		1.4
ClinPred		0.47	T
GERP RS		5.6
Varity_R		0.78
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783785; hg19: chrX-149828866;