13-25253774-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004685.5(MTMR6):c.1336G>A(p.Glu446Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTMR6 NM_004685.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

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=0.39639893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTMR6	NM_004685.5	c.1336G>A	p.Glu446Lys	missense_variant	11/14	ENST00000381801.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR6	ENST00000381801.6	c.1336G>A	p.Glu446Lys	missense_variant	11/14	1	NM_004685.5	P1
MTMR6	ENST00000482345.2	c.1450G>A	p.Glu484Lys	missense_variant	12/15	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2022

The c.1336G>A (p.E446K) alteration is located in exon 11 (coding exon 11) of the MTMR6 gene. This alteration results from a G to A substitution at nucleotide position 1336, causing the glutamic acid (E) at amino acid position 446 to be replaced by a lysine (K). 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	0.27
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.86	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.64	T
Sift4G	Benign	0.79	T
Polyphen		0.039	B
Vest4		0.57
MutPred		0.32		Loss of ubiquitination at K443 (P = 0.0272);
MVP		0.94
MPC		0.16
ClinPred		0.72	D
GERP RS		5.0
Varity_R		0.46
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-25827912;