chr1-155140033-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP3_ModerateBS1_Supporting
The NM_153741.2(DPM3):c.208G>A(p.Ala70Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,864 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 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
DPM3
NM_153741.2 missense
NM_153741.2 missense
Scores
6
7
5
Clinical Significance
Conservation
PhyloP100: 6.91
Genes affected
DPM3 (HGNC:3007): (dolichyl-phosphate mannosyltransferase subunit 3, 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 subunit of dolichyl-phosphate mannosyltransferase and acts as a stabilizer subunit of the dolichyl-phosphate mannosyltransferase complex. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
In a chain Dolichol-phosphate mannosyltransferase subunit 3 (size 91) in uniprot entity DPM3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_153741.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000197 (3/152230) while in subpopulation SAS AF= 0.000414 (2/4832). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DPM3 | NM_153741.2 | c.208G>A | p.Ala70Thr | missense_variant | 2/2 | ENST00000368400.5 | NP_714963.1 | |
DPM3 | NM_018973.4 | c.298G>A | p.Ala100Thr | missense_variant | 1/1 | NP_061846.2 | ||
DPM3 | XM_017001498.2 | c.208G>A | p.Ala70Thr | missense_variant | 2/2 | XP_016856987.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DPM3 | ENST00000368400.5 | c.208G>A | p.Ala70Thr | missense_variant | 2/2 | 1 | NM_153741.2 | ENSP00000357385 | P1 | |
DPM3 | ENST00000368399.1 | c.298G>A | p.Ala100Thr | missense_variant | 1/1 | ENSP00000357384 | ||||
DPM3 | ENST00000341298.3 | c.208G>A | p.Ala70Thr | missense_variant | 2/2 | 2 | ENSP00000344338 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250764Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135636
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461634Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727134
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
DPM3-congenital disorder of glycosylation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2020 | This variant has not been reported in the literature in individuals with DPM3-related conditions. This variant is present in population databases (rs776662775, ExAC 0.01%). This sequence change replaces alanine with threonine at codon 70 of the DPM3 protein (p.Ala70Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. 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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Benign
D;T;T
Sift4G
Benign
T;T;T
Polyphen
1.0
.;D;D
Vest4
MutPred
0.80
.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at