rs1557412510

Variant names:

• chrX-150592630-A-G
• rs1557412510
• NM_000252.3:c.16A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000252.3(MTM1):​c.16A>G​(p.Thr6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,086,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T6T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0980
• 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, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08551869).
• BP6: Variant X-150592630-A-G is Benign according to our data. Variant chrX-150592630-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2992698.

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.16A>G	p.Thr6Ala	missense	Exon 2 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.16A>G	p.Thr6Ala	missense	Exon 2 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.16A>G	p.Thr6Ala	missense	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.16A>G	p.Thr6Ala	missense	Exon 2 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.16A>G	p.Thr6Ala	missense	Exon 2 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.16A>G	p.Thr6Ala	missense	Exon 2 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111799 Hom.: 0 Cov.: 22

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182770 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1086099 Hom.: 0 Cov.: 26 AF XY: 0.00000284 AC XY: 1 AN XY: 352589

African (AFR) AF: 0.00 AC: 0 AN: 26195

American (AMR) AF: 0.00 AC: 0 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19284

East Asian (EAS) AF: 0.00 AC: 0 AN: 30140

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 831497

Other (OTH) AF: 0.00 AC: 0 AN: 45698

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 111799 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33975

African (AFR) AF: 0.00 AC: 0 AN: 30730

American (AMR) AF: 0.00 AC: 0 AN: 10507

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6021

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53167

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.9
DANN	Benign	0.40
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.098
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.30
Sift	Benign	0.66	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.11		Loss of phosphorylation at T6 (P = 0.0308)
MVP		0.83
MPC		0.61
ClinPred		0.0091	T
GERP RS		-1.0
Varity_R		0.047
gMVP		0.64
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1557412510; hg19: chrX-149761092;