22-30007207-G-T

Variant summary

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

The NM_021090.4(MTMR3):c.765G>T(p.Gln255His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTMR3 NM_021090.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64

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]

(HGNC:):

ACMG classification

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/exons	MANE	UniProt
MTMR3	NM_021090.4	c.765G>T	p.Gln255His	missense_variant	10/20	ENST00000401950.7
MTMR3	NM_153050.3	c.765G>T	p.Gln255His	missense_variant	10/20
MTMR3	NM_153051.3	c.765G>T	p.Gln255His	missense_variant	10/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR3	ENST00000401950.7	c.765G>T	p.Gln255His	missense_variant	10/20	1	NM_021090.4	P4
	ENST00000624945.1	n.21030C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Sep 01, 2021

The c.765G>T (p.Q255H) alteration is located in exon 10 (coding exon 8) of the MTMR3 gene. This alteration results from a G to T substitution at nucleotide position 765, causing the glutamine (Q) at amino acid position 255 to be replaced by a histidine (H). 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;D;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T;T;T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.014	D;D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;D;D
Polyphen		0.99	D;D;.;D;D
Vest4		0.44
MutPred		0.54		Gain of disorder (P = 0.2016);Gain of disorder (P = 0.2016);.;Gain of disorder (P = 0.2016);Gain of disorder (P = 0.2016);
MVP		0.92
MPC		2.0
ClinPred		0.93	D
GERP RS		2.6
Varity_R		0.13
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-30403196;