5-32235002-G-A

Variant names:

• chr5-32235002-G-A
• NM_001040446.3:c.1472C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001040446.3(MTMR12):​c.1472C>T​(p.Thr491Ile) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T491N) has been classified 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: 9.59

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]

RNU6-1079P (HGNC:48042): (RNA, U6 small nuclear 1079, pseudogene)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR12	NM_001040446.3	c.1472C>T	p.Thr491Ile	missense_variant	Exon 14 of 16	ENST00000382142.8	NP_001035536.1
MTMR12	NM_001294343.2	c.1472C>T	p.Thr491Ile	missense_variant	Exon 14 of 15		NP_001281272.1
MTMR12	NM_001294344.2	c.1344+3999C>T		intron_variant	Intron 13 of 13		NP_001281273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR12	ENST00000382142.8	c.1472C>T	p.Thr491Ile	missense_variant	Exon 14 of 16	1	NM_001040446.3	ENSP00000371577.3
MTMR12	ENST00000280285.9	c.1472C>T	p.Thr491Ile	missense_variant	Exon 14 of 15	1		ENSP00000280285.5
MTMR12	ENST00000264934.5	c.1344+3999C>T		intron_variant	Intron 13 of 13	2		ENSP00000264934.5
RNU6-1079P	ENST00000362861.1	n.-127C>T		upstream_gene_variant		6

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

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1472C>T (p.T491I) alteration is located in exon 14 (coding exon 14) of the MTMR12 gene. This alteration results from a C to T substitution at nucleotide position 1472, causing the threonine (T) at amino acid position 491 to be replaced by an isoleucine (I). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.1	H;H
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.88	P;D
Vest4		0.98
MutPred		0.76		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.89

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: chr5-32235108;