22-30019706-G-C

Variant names:

• chr22-30019706-G-C
• rs371788373
• NM_021090.4:c.2047G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021090.4(MTMR3):​c.2047G>C​(p.Gly683Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTMR3 NM_021090.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.58

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR3	NM_021090.4	c.2047G>C	p.Gly683Arg	missense_variant	Exon 17 of 20	ENST00000401950.7	NP_066576.1
MTMR3	NM_153050.3	c.2047G>C	p.Gly683Arg	missense_variant	Exon 17 of 20		NP_694690.1
MTMR3	NM_153051.3	c.2047G>C	p.Gly683Arg	missense_variant	Exon 17 of 19		NP_694691.1
HORMAD2-AS1	NR_110541.2	n.362-977C>G		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR3	ENST00000401950.7	c.2047G>C	p.Gly683Arg	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.;T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.7	L;L;.;L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		1.0	D;D;.;D;D
Vest4		0.85
MutPred		0.31		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);.;Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.96
MPC		0.62
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.49

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: rs371788373; hg19: chr22-30415695;