Genetic Variant MTMR12:p.Val742Met (chr5-32229798-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001040446.3(MTMR12):c.2224G>A(p.Val742Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,545,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

MTMR12
NM_001040446.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95

Variant links:

Genes affected

MTMR12 (HGNC:18191): (myotubularin related protein 12) Phosphatidylinositide 3-kinase-derived membrane-anchored phosphatidylinositides, such as phosphatidylinositol 3-phosphate (PtdIns(3)P), regulate diverse cellular processes. The protein encoded by this gene functions as an adaptor subunit in a complex with an active PtdIns(3)P 3-phosphatase. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

MTMR12 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019643784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR12	NM_001040446.3 link	c.2224G>A	p.Val742Met	missense_variant	Exon 16 of 16	ENST00000382142.8	NP_001035536.1	Q9C0I1-1
MTMR12	NM_001294343.2 link	c.2062G>A	p.Val688Met	missense_variant	Exon 15 of 15		NP_001281272.1	Q9C0I1-2
MTMR12	NM_001294344.2 link	c.1894G>A	p.Val632Met	missense_variant	Exon 14 of 14		NP_001281273.1	Q9C0I1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTMR12	ENST00000382142.8 link	c.2224G>A	p.Val742Met	missense_variant	Exon 16 of 16	1	NM_001040446.3	ENSP00000371577.3	Q9C0I1-1
MTMR12	ENST00000280285.9 link	c.2062G>A	p.Val688Met	missense_variant	Exon 15 of 15	1		ENSP00000280285.5	Q9C0I1-2
MTMR12	ENST00000264934.5 link	c.1894G>A	p.Val632Met	missense_variant	Exon 14 of 14	2		ENSP00000264934.5	Q9C0I1-3

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000707

AC:

141

AN:

199488

Hom.:

AF XY:

0.000728

AC XY:

AN XY:

105700

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.000158

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000108

Gnomad FIN exome

AF:

0.000106

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.000638

GnomAD4 exome

AF:

0.00123

AC:

1708

AN:

1392906

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

800

AN XY:

685292

show subpopulations

Gnomad4 AFR exome

AF:

0.000128

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.000368

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000403

Gnomad4 FIN exome

AF:

0.000254

Gnomad4 NFE exome

AF:

0.00149

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000584

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.000604

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.000701

AC:

Asia WGS

AF:

0.00144

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

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2224G>A (p.V742M) alteration is located in exon 16 (coding exon 16) of the MTMR12 gene. This alteration results from a G to A substitution at nucleotide position 2224, causing the valine (V) at amino acid position 742 to be replaced by a methionine (M). 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

0.22

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

.;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

0.81

.;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.74

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.054

T;T;T

Sift4G

Benign

0.067

T;T;T

Polyphen

0.13

B;B;D

Vest4

0.17

MVP

0.47

MPC

1.3

ClinPred

0.036

GERP RS

4.2

Varity_R

0.032

gMVP

0.25

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