22-30019793-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021090.4(MTMR3):c.2134A>G(p.Ile712Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,352 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 0.0000066 (0 hom., cov: 32)
• Consequence: MTMR3 NM_021090.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.72

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025865704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTMR3	NM_021090.4	c.2134A>G	p.Ile712Val	missense_variant	17/20	ENST00000401950.7
HORMAD2-AS1	NR_110541.2	n.362-1064T>C		intron_variant, non_coding_transcript_variant
MTMR3	NM_153050.3	c.2134A>G	p.Ile712Val	missense_variant	17/20
MTMR3	NM_153051.3	c.2134A>G	p.Ile712Val	missense_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR3	ENST00000401950.7	c.2134A>G	p.Ile712Val	missense_variant	17/20	1	NM_021090.4	P4
	ENST00000624945.1	n.8444T>C		non_coding_transcript_exon_variant	1/1
HORMAD2-AS1	ENST00000429350.5	n.335-1064T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74510

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

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

Apr 25, 2022

The c.2134A>G (p.I712V) 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 2134, causing the isoleucine (I) at amino acid position 712 to be replaced by a valine (V). 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	0.061
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.059
Dann	Benign	0.43
DEOGEN2	Benign	0.19	T;.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.57	T;T;T;T;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.34	N;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.24	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.029
MutPred		0.15		Gain of methylation at R709 (P = 0.5181);Gain of methylation at R709 (P = 0.5181);.;Gain of methylation at R709 (P = 0.5181);Gain of methylation at R709 (P = 0.5181);
MVP		0.26
MPC		0.098
ClinPred		0.035	T
GERP RS		-11
Varity_R		0.023
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs555413140; hg19: chr22-30415782;