NM_021090.4:c.1819C>T

Variant names:

• chr22-30018071-C-T
• rs976261829
• NM_021090.4:c.1819C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021090.4(MTMR3):​c.1819C>T​(p.Arg607Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000825 in 1,453,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: MTMR3 NM_021090.4 missense, splice_region
• Scores: Splicing: ADA: 0.9932
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.35
• Publications: 1 publications found

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]

HORMAD2-AS1 (HGNC:50729): (HORMAD2 and MTMR3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR3	NM_021090.4	MANE Select	c.1819C>T	p.Arg607Trp	missense splice_region	Exon 16 of 20	NP_066576.1	Q13615-1
	MTMR3	NM_153050.3		c.1819C>T	p.Arg607Trp	missense splice_region	Exon 16 of 20	NP_694690.1	Q13615-2
	MTMR3	NM_153051.3		c.1819C>T	p.Arg607Trp	missense splice_region	Exon 16 of 19	NP_694691.1	Q13615-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR3	ENST00000401950.7	TSL:1 MANE Select	c.1819C>T	p.Arg607Trp	missense splice_region	Exon 16 of 20	ENSP00000384651.3	Q13615-1
	MTMR3	ENST00000351488.7	TSL:1	c.1819C>T	p.Arg607Trp	missense splice_region	Exon 16 of 19	ENSP00000307271.6	Q13615-3
	MTMR3	ENST00000956491.1		c.1921C>T	p.Arg641Trp	missense splice_region	Exon 17 of 21	ENSP00000626550.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241346 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000825 AC: 12 AN: 1453958 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 4 AN XY: 723404

African (AFR) AF: 0.00 AC: 0 AN: 33070

American (AMR) AF: 0.00 AC: 0 AN: 42260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85086

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109356

Other (OTH) AF: 0.0000333 AC: 2 AN: 59978

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Myopathy, proximal, and ophthalmoplegia (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.32		Loss of solvent accessibility (P = 0.0036)
MVP		0.88
MPC		0.58
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.51
gMVP		0.55
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.91
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

Other links and lift over

dbSNP: rs976261829; hg19: chr22-30414060; COSMIC: COSV60308201; COSMIC: COSV60308201;