chr5-32229798-C-T

Variant names:

• chr5-32229798-C-T
• rs139269595
• NM_001040446.3:c.2224G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001040446.3(MTMR12):​c.2224G>A​(p.Val742Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,545,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: MTMR12 NM_001040446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019643784).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040446.3. 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
	MTMR12	NM_001040446.3	MANE Select	c.2224G>A	p.Val742Met	missense	Exon 16 of 16	NP_001035536.1	Q9C0I1-1
	MTMR12	NM_001294343.2		c.2062G>A	p.Val688Met	missense	Exon 15 of 15	NP_001281272.1	Q9C0I1-2
	MTMR12	NM_001294344.2		c.1894G>A	p.Val632Met	missense	Exon 14 of 14	NP_001281273.1	Q9C0I1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR12	ENST00000382142.8	TSL:1 MANE Select	c.2224G>A	p.Val742Met	missense	Exon 16 of 16	ENSP00000371577.3	Q9C0I1-1
	MTMR12	ENST00000280285.9	TSL:1	c.2062G>A	p.Val688Met	missense	Exon 15 of 15	ENSP00000280285.5	Q9C0I1-2
	MTMR12	ENST00000851378.1		c.2368G>A	p.Val790Met	missense	Exon 17 of 17	ENSP00000521437.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000707 AC: 141 AN: 199488 AF XY: 0.000728

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.000158

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.000638

GnomAD4 exome AF: 0.00123 AC: 1708 AN: 1392906 Hom.: 1 Cov.: 31 AF XY: 0.00117 AC XY: 800 AN XY: 685292

African (AFR) AF: 0.000128 AC: 4 AN: 31292

American (AMR) AF: 0.000233 AC: 8 AN: 34310

Ashkenazi Jewish (ASJ) AF: 0.000368 AC: 8 AN: 21710

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 38988

South Asian (SAS) AF: 0.0000403 AC: 3 AN: 74526

European-Finnish (FIN) AF: 0.000254 AC: 13 AN: 51220

Middle Eastern (MID) AF: 0.000370 AC: 2 AN: 5406

European-Non Finnish (NFE) AF: 0.00149 AC: 1605 AN: 1077980

Other (OTH) AF: 0.00111 AC: 64 AN: 57474

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74462

African (AFR) AF: 0.000144 AC: 6 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.000701 AC: 85

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.81	L
PhyloP100		2.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.28
Sift	Benign	0.054	T
Sift4G	Benign	0.067	T
Polyphen		0.13	B
Vest4		0.17
MVP		0.47
MPC		1.3
ClinPred		0.036	T
GERP RS		4.2
Varity_R		0.032
gMVP		0.25
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs139269595; hg19: chr5-32229904; COSMIC: COSV99373533; COSMIC: COSV99373533;