Genetic Variant NM_004685.5:c.1258G>C (chr13-25253852-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004685.5(MTMR6):c.1258G>C(p.Ala420Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MTMR6
NM_004685.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.27

Variant links:

Genes affected

MTMR6 (HGNC:7453): (myotubularin related protein 6) Enables phosphatidylinositol-3,5-bisphosphate phosphatase activity and phosphatidylinositol-3-phosphatase activity. Involved in phosphatidylinositol dephosphorylation. Located in cytoplasm and nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

MTMR6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR6	NM_004685.5 link	c.1258G>C	p.Ala420Pro	missense_variant	Exon 11 of 14	ENST00000381801.6	NP_004676.3	Q9Y217-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR6	ENST00000381801.6 link	c.1258G>C	p.Ala420Pro	missense_variant	Exon 11 of 14	1	NM_004685.5	ENSP00000371221.5		Q9Y217-1
MTMR6	ENST00000482345.2 link	c.1372G>C	p.Ala458Pro	missense_variant	Exon 12 of 15	5		ENSP00000516657.1		A0A9L9PXJ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251336

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1258G>C (p.A420P) alteration is located in exon 11 (coding exon 11) of the MTMR6 gene. This alteration results from a G to C substitution at nucleotide position 1258, causing the alanine (A) at amino acid position 420 to be replaced by a proline (P). 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

0.19

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.56

Sift

Benign

0.099

Sift4G

Benign

0.18

Polyphen

0.19

Vest4

0.68

MutPred

0.42

Loss of helix (P = 0.079);

MVP

0.98

MPC

0.21

ClinPred

0.42

GERP RS

5.0

Varity_R

0.81

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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