X-150592620-T-G

Variant names:

• chrX-150592620-T-G
• rs946865351
• NM_000252.3:c.6T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000252.3(MTM1):​c.6T>G​(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,196,976 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 0 hem.)
• Consequence: MTM1 NM_000252.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0900
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-150592620-T-G is Benign according to our data. Variant chrX-150592620-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2918731.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.09 with no splicing effect.

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.6T>G	p.Ala2Ala	synonymous	Exon 2 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.6T>G	p.Ala2Ala	synonymous	Exon 2 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.6T>G	p.Ala2Ala	synonymous	Exon 2 of 15	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.6T>G	p.Ala2Ala	synonymous	Exon 2 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.6T>G	p.Ala2Ala	synonymous	Exon 2 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.6T>G	p.Ala2Ala	synonymous	Exon 2 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111895 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000369 AC: 4 AN: 1085081 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 351863

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26177

American (AMR) AF: 0.00 AC: 0 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19298

East Asian (EAS) AF: 0.00 AC: 0 AN: 30133

South Asian (SAS) AF: 0.00 AC: 0 AN: 53871

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00000482 AC: 4 AN: 830517

Other (OTH) AF: 0.00 AC: 0 AN: 45661

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0132501), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111895 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34073

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30750

American (AMR) AF: 0.00 AC: 0 AN: 10517

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53200

Other (OTH) AF: 0.00 AC: 0 AN: 1507

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.2
DANN	Benign	0.69
PhyloP100		0.090

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

Other links and lift over

dbSNP: rs946865351; hg19: chrX-149761082;