22-30007267-G-T

Position:

• chr22-30007267-G-T

Variant summary

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

The ENST00000401950.7(MTMR3):​c.825G>T​(p.Arg275Ser) 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 ENST00000401950.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122078925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR3	NM_021090.4	c.825G>T	p.Arg275Ser	missense_variant	10/20	ENST00000401950.7	NP_066576.1
MTMR3	NM_153050.3	c.825G>T	p.Arg275Ser	missense_variant	10/20		NP_694690.1
MTMR3	NM_153051.3	c.825G>T	p.Arg275Ser	missense_variant	10/19		NP_694691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR3	ENST00000401950.7	c.825G>T	p.Arg275Ser	missense_variant	10/20	1	NM_021090.4	ENSP00000384651	P4
	ENST00000624945.1	n.20970C>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

Jun 29, 2022

The c.825G>T (p.R275S) 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 825, causing the arginine (R) at amino acid position 275 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T;.;T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D;.
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.76	N;N;.;N;N
MutationTaster	Benign	0.72	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.75	N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.71	T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.0040	B;B;.;B;B
Vest4		0.36
MutPred		0.41		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.85
MPC		1.4
ClinPred		0.26	T
GERP RS		2.2
Varity_R		0.062
gMVP		0.64

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: chr22-30403256;