chr22-30018071-C-T

Position:

• chr22-30018071-C-T

Variant summary

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

The ENST00000401950.7(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: MTMR3 ENST00000401950.7 missense, splice_region
• Scores: Splicing: ADA: 0.9932
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.35

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 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, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR3	NM_021090.4	c.1819C>T	p.Arg607Trp	missense_variant, splice_region_variant	16/20	ENST00000401950.7	NP_066576.1
HORMAD2-AS1	NR_110541.2	n.474+546G>A		intron_variant, non_coding_transcript_variant
MTMR3	NM_153050.3	c.1819C>T	p.Arg607Trp	missense_variant, splice_region_variant	16/20		NP_694690.1
MTMR3	NM_153051.3	c.1819C>T	p.Arg607Trp	missense_variant, splice_region_variant	16/19		NP_694691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR3	ENST00000401950.7	c.1819C>T	p.Arg607Trp	missense_variant, splice_region_variant	16/20	1	NM_021090.4	ENSP00000384651	P4
	ENST00000624945.1	n.10166G>A		non_coding_transcript_exon_variant	1/1
HORMAD2-AS1	ENST00000429350.5	n.447+546G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000414 AC: 1 AN: 241346 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130818

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;.
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.3	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.82
MutPred		0.32		Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);.;Loss of solvent accessibility (P = 0.0036);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

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

Publications

LitVar

Other links and lift over

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