rs185258809

Variant names:

• chrX-150658044-A-G
• rs185258809
• NM_000252.3:c.1260+17A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000252.3(MTM1):​c.1260+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00896 in 1,115,153 control chromosomes in the GnomAD database, including 44 homozygotes. There are 3,073 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0066 (5 hom., 237 hem., cov: 23)
  • Exomes 𝑓: 0.0092 (39 hom. 2836 hem.)
• Consequence: MTM1 NM_000252.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.607
• Publications: 0 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-150658044-A-G is Benign according to our data. Variant chrX-150658044-A-G is described in ClinVar as Benign. ClinVar VariationId is 255621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00661 (744/112605) while in subpopulation NFE AF = 0.00885 (472/53326). AF 95% confidence interval is 0.00819. There are 5 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 XL gene

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.1260+17A>G		intron	N/A	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1260+17A>G		intron	N/A	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1260+17A>G		intron	N/A	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.1260+17A>G		intron	N/A	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1305+17A>G		intron	N/A	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1305+17A>G		intron	N/A	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 744 AN: 112551 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0701

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.00725

GnomAD2 exomes AF: 0.00670 AC: 1169 AN: 174442 AF XY: 0.00651

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.00337

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.00925

Gnomad OTH exome AF: 0.00368

GnomAD4 exome AF: 0.00922 AC: 9246 AN: 1002548 Hom.: 39 Cov.: 22 AF XY: 0.00996 AC XY: 2836 AN XY: 284744

African (AFR) AF: 0.000741 AC: 18 AN: 24305

American (AMR) AF: 0.00289 AC: 101 AN: 34915

Ashkenazi Jewish (ASJ) AF: 0.00197 AC: 37 AN: 18750

East Asian (EAS) AF: 0.00 AC: 0 AN: 29744

South Asian (SAS) AF: 0.00175 AC: 90 AN: 51385

European-Finnish (FIN) AF: 0.0175 AC: 706 AN: 40240

Middle Eastern (MID) AF: 0.000770 AC: 3 AN: 3896

European-Non Finnish (NFE) AF: 0.0106 AC: 7991 AN: 756348

Other (OTH) AF: 0.00698 AC: 300 AN: 42965

GnomAD4 genome AF: 0.00661 AC: 744 AN: 112605 Hom.: 5 Cov.: 23 AF XY: 0.00682 AC XY: 237 AN XY: 34747

African (AFR) AF: 0.00145 AC: 45 AN: 31035

American (AMR) AF: 0.00197 AC: 21 AN: 10636

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 5 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3613

South Asian (SAS) AF: 0.00 AC: 0 AN: 2767

European-Finnish (FIN) AF: 0.0232 AC: 142 AN: 6130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00885 AC: 472 AN: 53326

Other (OTH) AF: 0.00716 AC: 11 AN: 1536

Alfa AF: 0.00689 Hom.: 58

Bravo AF: 0.00544

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.022
DANN	Benign	0.70
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs185258809;

hg19: chrX-149826517;