13-25253774-C-T

Variant names:

• chr13-25253774-C-T
• NM_004685.5:c.1336G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E446G) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39639893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004685.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR6	NM_004685.5	MANE Select	c.1336G>A	p.Glu446Lys	missense	Exon 11 of 14	NP_004676.3
	MTMR6	NM_001385230.1		c.1450G>A	p.Glu484Lys	missense	Exon 12 of 15	NP_001372159.1	A0A9L9PXJ0
	MTMR6	NM_001385231.1		c.1282G>A	p.Glu428Lys	missense	Exon 11 of 14	NP_001372160.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR6	ENST00000381801.6	TSL:1 MANE Select	c.1336G>A	p.Glu446Lys	missense	Exon 11 of 14	ENSP00000371221.5	Q9Y217-1
	MTMR6	ENST00000482345.2	TSL:5	c.1450G>A	p.Glu484Lys	missense	Exon 12 of 15	ENSP00000516657.1	A0A9L9PXJ0
	MTMR6	ENST00000956555.1		c.1336G>A	p.Glu446Lys	missense	Exon 11 of 15	ENSP00000626614.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.9
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
Mutation Taster		=43/57	disease causing

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

Other links and lift over

hg19: chr13-25827912;