rs201904466

Positions:

chr3-9672734-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001077525.3(MTMR14):c.727A>G(p.Thr243Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

MTMR14
NM_001077525.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 8.58

Variant links:

Genes affected

MTMR14 (HGNC:26190): (myotubularin related protein 14) This gene encodes a myotubularin-related protein. The encoded protein is a phosphoinositide phosphatase that specifically dephosphorylates phosphatidylinositol 3,5-biphosphate and phosphatidylinositol 3-phosphate. Mutations in this gene are correlated with autosomal dominant centronuclear myopathy. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 18.[provided by RefSeq, Apr 2010]

MTMR14 links:

MTMR14 (HGNC:):

MTMR14 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4128163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR14	NM_001077525.3 linkuse as main transcript	c.727A>G	p.Thr243Ala	missense_variant	7/19	ENST00000296003.9	NP_001070993.1	Q8NCE2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR14	ENST00000296003.9 linkuse as main transcript	c.727A>G	p.Thr243Ala	missense_variant	7/19	1	NM_001077525.3	ENSP00000296003.5		Q8NCE2-1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0000657

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:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000244

AC:

AN:

249570

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000503

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000540

AC:

789

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

383

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000689

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000375

AC:

AN:

151904

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000455

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.000207

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 243 of the MTMR14 protein (p.Thr243Ala). This variant is present in population databases (rs201904466, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MTMR14-related conditions. ClinVar contains an entry for this variant (Variation ID: 377092). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MTMR14 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 02, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.727A>G (p.T243A) alteration is located in exon 7 (coding exon 7) of the MTMR14 gene. This alteration results from a A to G substitution at nucleotide position 727, causing the threonine (T) at amino acid position 243 to be replaced by an alanine (A). 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

0.13

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

N;N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.042

D;D;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.92

P;P;D

Vest4

0.79

MVP

0.94

MPC

0.77

ClinPred

0.11

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.74

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over