22-30019883-G-T

Variant names:

• chr22-30019883-G-T
• NM_021090.4:c.2224G>T

Variant summary

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

The NM_021090.4(MTMR3):​c.2224G>T​(p.Asp742Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: 1.14

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]

ENSG00000279159 (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=0.105869114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR3	NM_021090.4	c.2224G>T	p.Asp742Tyr	missense_variant	Exon 17 of 20	ENST00000401950.7	NP_066576.1
MTMR3	NM_153050.3	c.2224G>T	p.Asp742Tyr	missense_variant	Exon 17 of 20		NP_694690.1
MTMR3	NM_153051.3	c.2224G>T	p.Asp742Tyr	missense_variant	Exon 17 of 19		NP_694691.1
HORMAD2-AS1	NR_110541.2	n.362-1154C>A		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR3	ENST00000401950.7	c.2224G>T	p.Asp742Tyr	missense_variant	Exon 17 of 20	1	NM_021090.4	ENSP00000384651.3

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

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2224G>T (p.D742Y) alteration is located in exon 17 (coding exon 15) of the MTMR3 gene. This alteration results from a G to T substitution at nucleotide position 2224, causing the aspartic acid (D) at amino acid position 742 to be replaced by a tyrosine (Y). 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	0.081
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.33	T;.;T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.91	D;D;D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.0	N;N;.;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		0.10	B;B;.;B;B
Vest4		0.16
MutPred		0.36		Loss of disorder (P = 0.031);Loss of disorder (P = 0.031);.;Loss of disorder (P = 0.031);Loss of disorder (P = 0.031);
MVP		0.54
MPC		0.20
ClinPred		0.19	T
GERP RS		1.8
Varity_R		0.16
gMVP		0.24

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: chr22-30415872; COSMIC: COSV60302758; COSMIC: COSV60302758;