Genetic Variant TMEM186:p.Ala113Asp (chr16-8796256-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_015421.4(TMEM186):c.338C>A(p.Ala113Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

TMEM186
NM_015421.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.11

Publications

2 publications found

Variant links:

Genes affected

TMEM186 (HGNC:24530): (transmembrane protein 186) This gene encodes a potential transmembrane protein. [provided by RefSeq, Dec 2012]

TMEM186 links:

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]

PMM2 Gene-Disease associations (from GenCC):

congenital disorder of glycosylation type I
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
PMM2-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
hyperinsulinemic hypoglycemia with polycystic kidney disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

PMM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015421.4. 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
	TMEM186	NM_015421.4	MANE Select	c.338C>A	p.Ala113Asp	missense	Exon 2 of 2	NP_056236.2	Q96B77

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM186	ENST00000333050.7	TSL:1 MANE Select	c.338C>A	p.Ala113Asp	missense	Exon 2 of 2	ENSP00000331640.6	Q96B77
TMEM186	ENST00000872296.1		c.56C>A	p.Ala19Asp	missense	Exon 2 of 2	ENSP00000542355.1
PMM2	ENST00000566983.5	TSL:5	c.-15-5543G>T		intron	N/A	ENSP00000457956.1	H3BV55

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000243

AC:

AN:

251398

AF XY:

0.000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000518

AC:

757

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

382

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000625

AC:

695

AN:

1112012

Other (OTH)

AF:

0.000563

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000289

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41434

American (AMR)

AF:

0.000459

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68040

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000540

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.73

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

3.0

PhyloP100

8.1

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.60

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.37

MPC

0.27

ClinPred

0.82

GERP RS

5.2

Varity_R

0.85

gMVP

0.96

Mutation Taster

=22/78

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over