dbSNP rs117175017: DPM1:p.Arg14Trp (chr20-50958484-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003859.3(DPM1):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,613,936 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R14R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 5 hom. )

Consequence

DPM1
NM_003859.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.78

Publications

6 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 Gene-Disease associations (from GenCC):

congenital disorder of glycosylation type 1E
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, ClinGen, Orphanet

DPM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006441295).

BP6

Variant 20-50958484-G-A is Benign according to our data. Variant chr20-50958484-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 338758.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00161 (245/152236) while in subpopulation NFE AF = 0.00246 (167/68004). AF 95% confidence interval is 0.00215. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

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.40C>T	p.Arg14Trp	missense	Exon 1 of 9	NP_003850.1	O60762
DPM1	NM_001317034.1		c.40C>T	p.Arg14Trp	missense	Exon 1 of 10	NP_001303963.1	O60762
DPM1	NM_001317035.1		c.40C>T	p.Arg14Trp	missense	Exon 1 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.40C>T	p.Arg14Trp	missense	Exon 1 of 9	ENSP00000360644.5	O60762
DPM1	ENST00000371582.8	TSL:1	c.40C>T	p.Arg14Trp	missense	Exon 1 of 10	ENSP00000360638.4	Q5QPK2
DPM1	ENST00000466152.5	TSL:1	n.40C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000507119.1	A0A804HIK9

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

245

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00246

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00164

AC:

412

AN:

251296

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00298

Gnomad NFE exome

AF:

0.00249

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00279

AC:

4080

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1979

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.00145

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00248

AC:

132

AN:

53232

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00337

AC:

3750

AN:

1112008

Other (OTH)

AF:

0.00192

AC:

116

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

252

503

755

1006

1258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00161

AC:

245

AN:

152236

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41548

American (AMR)

AF:

0.00118

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00320

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00246

AC:

167

AN:

68004

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00211

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00163

AC:

198

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00308

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital disorder of glycosylation type 1E (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.76

M_CAP

Benign

0.013

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

1.8

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.92

REVEL

Benign

0.046

Sift

Uncertain

0.0050

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.27

MVP

0.54

MPC

0.27

ClinPred

0.075

GERP RS

2.4

PromoterAI

-0.16

Neutral

(source)

Varity_R

0.070

gMVP

0.69

Mutation Taster

=100/0

polymorphism

(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

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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