5-32233780-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001040446.3(MTMR12):​c.1667G>A​(p.Arg556His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R556C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MTMR12
NM_001040446.3 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.564
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007341087).
BP6
Variant 5-32233780-C-T is Benign according to our data. Variant chr5-32233780-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2356244.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTMR12NM_001040446.3 linkc.1667G>A p.Arg556His missense_variant Exon 15 of 16 ENST00000382142.8 NP_001035536.1 Q9C0I1-1
MTMR12NM_001294343.2 linkc.1512+1182G>A intron_variant Intron 14 of 14 NP_001281272.1 Q9C0I1-2
MTMR12NM_001294344.2 linkc.1345-3433G>A intron_variant Intron 13 of 13 NP_001281273.1 Q9C0I1-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTMR12ENST00000382142.8 linkc.1667G>A p.Arg556His missense_variant Exon 15 of 16 1 NM_001040446.3 ENSP00000371577.3 Q9C0I1-1
MTMR12ENST00000280285.9 linkc.1512+1182G>A intron_variant Intron 14 of 14 1 ENSP00000280285.5 Q9C0I1-2
MTMR12ENST00000264934.5 linkc.1345-3433G>A intron_variant Intron 13 of 13 2 ENSP00000264934.5 Q9C0I1-3
MTMR12ENST00000510216.1 linkn.114G>A non_coding_transcript_exon_variant Exon 1 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00576
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
53
AN:
251474
Hom.:
0
AF XY:
0.000243
AC XY:
33
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00427
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000527
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000129
AC:
188
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.000142
AC XY:
103
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00490
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00576
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000304
Hom.:
0
Bravo
AF:
0.000208
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Apr 25, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
16
DANN
Benign
0.92
DEOGEN2
Benign
0.022
T
Eigen
Benign
-0.96
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.85
D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.0073
T
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
0.61
N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.86
N
REVEL
Benign
0.22
Sift
Benign
0.10
T
Sift4G
Benign
0.29
T
Polyphen
0.0020
B
Vest4
0.26
MVP
0.37
MPC
0.59
ClinPred
0.021
T
GERP RS
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.051
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145260557; hg19: chr5-32233886; API