rs1324518346

Variant names:

• chr22-30019767-T-A
• rs1324518346
• NM_021090.4:c.2108T>A

Variant summary

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

The NM_021090.4(MTMR3):​c.2108T>A​(p.Val703Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 150,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: MTMR3 NM_021090.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.205

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=0.07786623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR3	NM_021090.4	c.2108T>A	p.Val703Glu	missense_variant	Exon 17 of 20	ENST00000401950.7	NP_066576.1
MTMR3	NM_153050.3	c.2108T>A	p.Val703Glu	missense_variant	Exon 17 of 20		NP_694690.1
MTMR3	NM_153051.3	c.2108T>A	p.Val703Glu	missense_variant	Exon 17 of 19		NP_694691.1
HORMAD2-AS1	NR_110541.2	n.362-1038A>T		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR3	ENST00000401950.7	c.2108T>A	p.Val703Glu	missense_variant	Exon 17 of 20	1	NM_021090.4	ENSP00000384651.3

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150898 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150898 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73640

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2108T>A (p.V703E) alteration is located in exon 17 (coding exon 15) of the MTMR3 gene. This alteration results from a T to A substitution at nucleotide position 2108, causing the valine (V) at amino acid position 703 to be replaced by a glutamic acid (E). 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	0.099
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	8.9
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.84	T;T;T;T;.
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.69	N;N;.;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.016	D;D;D;D;D
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.14	B;B;.;B;B
Vest4		0.34
MutPred		0.21		Gain of solvent accessibility (P = 0.0256);Gain of solvent accessibility (P = 0.0256);.;Gain of solvent accessibility (P = 0.0256);Gain of solvent accessibility (P = 0.0256);
MVP		0.66
MPC		0.22
ClinPred		0.13	T
GERP RS		-2.7
Varity_R		0.25
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1324518346; hg19: chr22-30415756;