5-32229807-C-A

Variant names:

• chr5-32229807-C-A
• NM_001040446.3:c.2215G>T

Variant summary

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

The NM_001040446.3(MTMR12):​c.2215G>T​(p.Asp739Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTMR12 NM_001040446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

Genes affected

MTMR12 (HGNC:18191): (myotubularin related protein 12) Phosphatidylinositide 3-kinase-derived membrane-anchored phosphatidylinositides, such as phosphatidylinositol 3-phosphate (PtdIns(3)P), regulate diverse cellular processes. The protein encoded by this gene functions as an adaptor subunit in a complex with an active PtdIns(3)P 3-phosphatase. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

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, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR12	NM_001040446.3	c.2215G>T	p.Asp739Tyr	missense_variant	Exon 16 of 16	ENST00000382142.8	NP_001035536.1
MTMR12	NM_001294343.2	c.2053G>T	p.Asp685Tyr	missense_variant	Exon 15 of 15		NP_001281272.1
MTMR12	NM_001294344.2	c.1885G>T	p.Asp629Tyr	missense_variant	Exon 14 of 14		NP_001281273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR12	ENST00000382142.8	c.2215G>T	p.Asp739Tyr	missense_variant	Exon 16 of 16	1	NM_001040446.3	ENSP00000371577.3
MTMR12	ENST00000280285.9	c.2053G>T	p.Asp685Tyr	missense_variant	Exon 15 of 15	1		ENSP00000280285.5
MTMR12	ENST00000264934.5	c.1885G>T	p.Asp629Tyr	missense_variant	Exon 14 of 14	2		ENSP00000264934.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2215G>T (p.D739Y) alteration is located in exon 16 (coding exon 16) of the MTMR12 gene. This alteration results from a G to T substitution at nucleotide position 2215, causing the aspartic acid (D) at amino acid position 739 to be replaced by a tyrosine (Y). 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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	0.97	.;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.60
MutPred		0.39		.;Loss of disorder (P = 9e-04);.;
MVP		0.76
MPC		1.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.77

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: chr5-32229913;