rs150430628

chrX-150649900-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_000252.3(MTM1):c.1052A>G(p.Lys351Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,192,902 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 152 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 7 hem., cov: 24)
  • Exomes 𝑓: 0.00041 (0 hom. 145 hem.)
• Consequence: MTM1 NM_000252.3 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 9.24

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 Benign. Variant got -8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747
• BP6: Variant X-150649900-A-G is Benign according to our data. Variant chrX-150649900-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500885.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000196 (22/112354) while in subpopulation NFE AF= 0.000338 (18/53276). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.1052A>G	p.Lys351Arg	missense_variant, splice_region_variant	10/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.1052A>G	p.Lys351Arg	missense_variant, splice_region_variant	10/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112354 Hom.: 0 Cov.: 24 AF XY: 0.000203 AC XY: 7 AN XY: 34500

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

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: 0.000338

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.000199 AC: 35 AN: 175656 Hom.: 0 AF XY: 0.000163 AC XY: 10 AN XY: 61422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000778

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000401

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000413 AC: 446 AN: 1080548 Hom.: 0 Cov.: 27 AF XY: 0.000418 AC XY: 145 AN XY: 347190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.000154

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112354 Hom.: 0 Cov.: 24 AF XY: 0.000203 AC XY: 7 AN XY: 34500

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000668

Alfa AF: 0.000433 Hom.: 3

Bravo AF: 0.000215

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000298 AC: 2

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2020	- -

Severe X-linked myotubular myopathy Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1052A>G (p.K351R) alteration is located in exon 10 (coding exon 9) of the MTM1 gene. This alteration results from a A to G substitution at nucleotide position 1052, causing the lysine (K) at amino acid position 351 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.57	N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.43
Sift	Benign	0.42	T
Sift4G	Benign	0.47	T
Polyphen		0.019	B
Vest4		0.77
MVP		0.99
MPC		1.5
ClinPred		0.19	T
GERP RS		5.7
Varity_R		0.54
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs150430628; hg19: chrX-149818373;