rs755055369

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2PP3_StrongBS1_Supporting

The NM_003863.4(DPM2):c.145T>A(p.Tyr49Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,540,610 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y49C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DPM2
NM_003863.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.54

Publications

0 publications found

Variant links:

Genes affected

DPM2 (HGNC:3006): (dolichyl-phosphate mannosyltransferase subunit 2, regulatory) Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. The protein encoded by this gene is a hydrophobic protein that contains 2 predicted transmembrane domains and a putative ER localization signal near the C terminus. This protein associates with DPM1 in vivo and is required for the ER localization and stable expression of DPM1 and also enhances the binding of dolichol-phosphate to DPM1. [provided by RefSeq, Jul 2008]

DPM2 Gene-Disease associations (from GenCC):

congenital muscular dystrophy with intellectual disability and severe epilepsy
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet

DPM2 links:

ENSG00000227218 (HGNC:):

ENSG00000227218 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000137 (19/1388432) while in subpopulation AMR AF = 0.0000586 (2/34104). AF 95% confidence interval is 0.00000971. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPM2	NM_003863.4 link	c.145T>A	p.Tyr49Asn	missense_variant	Exon 3 of 4	ENST00000314392.13	NP_003854.1	O94777

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPM2	ENST00000314392.13 link	c.145T>A	p.Tyr49Asn	missense_variant	Exon 3 of 4	1	NM_003863.4	ENSP00000322181.8		O94777

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

195152

AF XY:

0.0000383

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000822

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000216

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1388432

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

683316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30890

American (AMR)

AF:

0.0000586

AC:

AN:

34104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21742

East Asian (EAS)

AF:

0.00

AC:

AN:

37898

South Asian (SAS)

AF:

0.00

AC:

AN:

75952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5254

European-Non Finnish (NFE)

AF:

0.0000140

AC:

AN:

1074232

Other (OTH)

AF:

0.0000350

AC:

AN:

57184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital muscular dystrophy with intellectual disability and severe epilepsy

Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine with asparagine at codon 49 of the DPM2 protein (p.Tyr49Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs755055369, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with DPM2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

-0.056

PhyloP100

6.5

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-8.5

D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.93

MutPred

0.83

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);

MVP

0.84

MPC

2.1

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.88

Mutation Taster

=39/61

disease causing

(source)

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

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rs755055369

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over