chr20-50935214-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_003859.3(DPM1):c.701G>A(p.Arg234His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,606,626 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R234R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

DPM1
NM_003859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.37

Publications

1 publications found

Variant links:

Genes affected

DPM1 (HGNC:3005): (dolichyl-phosphate mannosyltransferase subunit 1, catalytic) 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. Human DPM1 lacks a carboxy-terminal transmembrane domain and signal sequence and is regulated by DPM2. Mutations in this gene are associated with congenital disorder of glycosylation type Ie. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

DPM1 links:

ADNP-AS1 (HGNC:51227): (ADNP antisense RNA 1)

ADNP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity DPM1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003859.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPM1	NM_003859.3	MANE Select	c.701G>A	p.Arg234His	missense	Exon 9 of 9	NP_003850.1	O60762
DPM1	NM_001317034.1		c.806G>A	p.Arg269His	missense	Exon 10 of 10	NP_001303963.1	O60762
DPM1	NM_001317035.1		c.782G>A	p.Arg261His	missense	Exon 10 of 10	NP_001303964.1	Q5QPK2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPM1	ENST00000371588.10	TSL:1 MANE Select	c.701G>A	p.Arg234His	missense	Exon 9 of 9	ENSP00000360644.5	O60762
DPM1	ENST00000371582.8	TSL:1	c.782G>A	p.Arg261His	missense	Exon 10 of 10	ENSP00000360638.4	Q5QPK2
DPM1	ENST00000466152.5	TSL:1	n.*156G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000507119.1	A0A804HIK9

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150098

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:

0.00

Gnomad OTH

AF:

0.000485

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250468

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1456528

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33272

American (AMR)

AF:

0.0000224

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39518

South Asian (SAS)

AF:

0.00

AC:

AN:

85994

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00000722

AC:

AN:

1107818

Other (OTH)

AF:

0.00

AC:

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150098

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40224

American (AMR)

AF:

0.00

AC:

AN:

15090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67812

Other (OTH)

AF:

0.000485

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital disorder of glycosylation type 1E (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

5.0

PhyloP100

7.4

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.90

MutPred

0.87

Gain of disorder (P = 0.0954)

MVP

0.74

MPC

0.91

ClinPred

0.98

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.72

gMVP

0.87

Mutation Taster

=14/86

disease causing

(source)

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

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