22-30019542-C-T

Position:

chr22-30019542-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000401950.7(MTMR3):c.1883C>T(p.Ala628Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,612,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MTMR3
ENST00000401950.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.92

Variant links:

Genes affected

MTMR3 (HGNC:7451): (myotubularin related protein 3) This gene encodes a member of the myotubularin dual specificity protein phosphatase gene family. The encoded protein is structurally similar to myotubularin but in addition contains a FYVE domain and an N-terminal PH-GRAM domain. The protein can self-associate and also form heteromers with another myotubularin related protein. The protein binds to phosphoinositide lipids through the PH-GRAM domain, and can hydrolyze phosphatidylinositol(3)-phosphate and phosphatidylinositol(3,5)-biphosphate in vitro. The encoded protein has been observed to have a perinuclear, possibly membrane-bound, distribution in cells, but it has also been found free in the cytoplasm. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MTMR3 links:

(HGNC:):

links:

HORMAD2-AS1 (HGNC:50729): (HORMAD2 and MTMR3 antisense RNA 1)

HORMAD2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09110835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MTMR3	NM_021090.4 linkuse as main transcript	c.1883C>T	p.Ala628Val	missense_variant	17/20	ENST00000401950.7	NP_066576.1
HORMAD2-AS1	NR_110541.2 linkuse as main transcript	n.362-813G>A		intron_variant, non_coding_transcript_variant
MTMR3	NM_153050.3 linkuse as main transcript	c.1883C>T	p.Ala628Val	missense_variant	17/20		NP_694690.1
MTMR3	NM_153051.3 linkuse as main transcript	c.1883C>T	p.Ala628Val	missense_variant	17/19		NP_694691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR3	ENST00000401950.7 linkuse as main transcript	c.1883C>T	p.Ala628Val	missense_variant	17/20	1	NM_021090.4	ENSP00000384651	P4	Q13615-1
	ENST00000624945.1 linkuse as main transcript	n.8695G>A		non_coding_transcript_exon_variant	1/1
HORMAD2-AS1	ENST00000429350.5 linkuse as main transcript	n.335-813G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

248730

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000329

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460124

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726340

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.1883C>T (p.A628V) alteration is located in exon 17 (coding exon 15) of the MTMR3 gene. This alteration results from a C to T substitution at nucleotide position 1883, causing the alanine (A) at amino acid position 628 to be replaced by a valine (V). 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

0.093

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

T;T;T;T;.

M_CAP

Benign

0.056

MetaRNN

Benign

0.091

T;T;T;T;T

MetaSVM

Uncertain

0.035

MutationAssessor

Benign

0.90

L;L;.;L;L

MutationTaster

Benign

0.84

D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

0.14

N;N;N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.36

T;T;T;T;T

Sift4G

Benign

0.54

T;T;T;T;T

Polyphen

0.011

B;B;.;B;B

Vest4

0.31

MutPred

0.21

Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);.;Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);

MVP

0.56

MPC

0.15

ClinPred

0.058

GERP RS

5.9

Varity_R

0.062

gMVP

0.32

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