rs200254657

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015421.4(TMEM186):​c.452G>T​(p.Arg151Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM186
NM_015421.4 missense

Scores

7
8
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.75
Variant links:
Genes affected
TMEM186 (HGNC:24530): (transmembrane protein 186) This gene encodes a potential transmembrane protein. [provided by RefSeq, Dec 2012]
PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM186NM_015421.4 linkc.452G>T p.Arg151Leu missense_variant Exon 2 of 2 ENST00000333050.7 NP_056236.2 Q96B77

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM186ENST00000333050.7 linkc.452G>T p.Arg151Leu missense_variant Exon 2 of 2 1 NM_015421.4 ENSP00000331640.6 Q96B77
PMM2ENST00000566983.5 linkc.-15-5657C>A intron_variant Intron 1 of 7 5 ENSP00000457956.1 H3BV55
TMEM186ENST00000564869.1 linkn.31+1470G>T intron_variant Intron 1 of 2 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.83
T
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Benign
-0.61
T
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Benign
0.40
T
PROVEAN
Pathogenic
-7.0
D
REVEL
Uncertain
0.42
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.79
MutPred
0.65
Loss of phosphorylation at T154 (P = 0.0541);
MVP
0.33
MPC
0.26
ClinPred
0.99
D
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.76
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-8889999; API