22-30019748-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021090.4(MTMR3):c.2089A>G(p.Thr697Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: MTMR3 NM_021090.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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:):

HORMAD2-AS1 (HGNC:50729): (HORMAD2 and MTMR3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21997148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTMR3	NM_021090.4	c.2089A>G	p.Thr697Ala	missense_variant	17/20	ENST00000401950.7
HORMAD2-AS1	NR_110541.2	n.362-1019T>C		intron_variant, non_coding_transcript_variant
MTMR3	NM_153050.3	c.2089A>G	p.Thr697Ala	missense_variant	17/20
MTMR3	NM_153051.3	c.2089A>G	p.Thr697Ala	missense_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR3	ENST00000401950.7	c.2089A>G	p.Thr697Ala	missense_variant	17/20	1	NM_021090.4	P4
	ENST00000624945.1	n.8489T>C		non_coding_transcript_exon_variant	1/1
HORMAD2-AS1	ENST00000429350.5	n.335-1019T>C		intron_variant, non_coding_transcript_variant		3

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

Feb 13, 2023

The c.2089A>G (p.T697A) alteration is located in exon 17 (coding exon 15) of the MTMR3 gene. This alteration results from a A to G substitution at nucleotide position 2089, causing the threonine (T) at amino acid position 697 to be replaced by an alanine (A). 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	0.091
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.35	T;.;T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D;D;.
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.8	L;L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.78	T;T;T;T;T
Polyphen		0.57	P;P;.;P;P
Vest4		0.39
MutPred		0.15		Loss of phosphorylation at T697 (P = 0.0305);Loss of phosphorylation at T697 (P = 0.0305);.;Loss of phosphorylation at T697 (P = 0.0305);Loss of phosphorylation at T697 (P = 0.0305);
MVP		0.84
MPC		0.16
ClinPred		0.43	T
GERP RS		3.7
Varity_R		0.071
gMVP		0.31

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: chr22-30415737;