Genetic Variant DPM1:p.Ile229Leu (chr20-50935230-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003859.3(DPM1):c.685A>T(p.Ile229Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 133,486 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I229V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000075 ( 0 hom., cov: 33)

Consequence

DPM1
NM_003859.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.47

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

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.685A>T	p.Ile229Leu	missense	Exon 9 of 9	NP_003850.1	O60762
DPM1	NM_001317034.1		c.790A>T	p.Ile264Leu	missense	Exon 10 of 10	NP_001303963.1	O60762
DPM1	NM_001317035.1		c.766A>T	p.Ile256Leu	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.685A>T	p.Ile229Leu	missense	Exon 9 of 9	ENSP00000360644.5	O60762
DPM1	ENST00000371582.8	TSL:1	c.766A>T	p.Ile256Leu	missense	Exon 10 of 10	ENSP00000360638.4	Q5QPK2
DPM1	ENST00000466152.5	TSL:1	n.*140A>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000507119.1	A0A804HIK9

Frequencies

GnomAD3 genomes

AF:

0.00000749

AC:

AN:

133486

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:

0.000218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000749

AC:

AN:

133486

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

64986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28610

American (AMR)

AF:

0.00

AC:

AN:

13810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3322

East Asian (EAS)

AF:

0.00

AC:

AN:

4930

South Asian (SAS)

AF:

0.000218

AC:

AN:

4578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65504

Other (OTH)

AF:

0.00

AC:

AN:

1878

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

4.5

PhyloP100

7.5

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.74

MutPred

0.68

Gain of catalytic residue at I229 (P = 0.0019)

MVP

0.70

MPC

0.33

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.46

gMVP

0.67

Mutation Taster

=36/64

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over