rs587777116

Variant names:

• chr20-50942070-C-A
• rs587777116
• NM_003859.3:c.455G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_003859.3(DPM1):​c.455G>T​(p.Gly152Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,834 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000639038: Experimental studies have shown that this missense change affects DPM1 function (PMID:23856421, 26729507)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G152G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DPM1 NM_003859.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.36
• Publications: 4 publications found

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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000639038: Experimental studies have shown that this missense change affects DPM1 function (PMID: 23856421, 26729507).; SCV003929337: "the variant abolishes binding to DPM3, a non-catalytic subunit of the DPM complex (Yang_2013), reduced activity by 70% in a zebrafish model (Ardiccioni_2016), and abolished activity when the orthologous residue was mutated in a cyanobacterium model (Ardiccioni_2016)." PMID: 31003021, 26729507, 28743912, 23856421; SCV005904717: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 23856421, 26729507)."; SCV003837073: Published functional studies demonstrate complete loss of function (PMID: 26729507, 23856421)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 20-50942070-C-A is Pathogenic according to our data. Variant chr20-50942070-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 100636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPM1	NM_003859.3	MANE Select	c.455G>T	p.Gly152Val	missense	Exon 6 of 9	NP_003850.1	O60762
	DPM1	NM_001317034.1		c.455G>T	p.Gly152Val	missense	Exon 6 of 10	NP_001303963.1	O60762
	DPM1	NM_001317035.1		c.455G>T	p.Gly152Val	missense	Exon 6 of 10	NP_001303964.1	Q5QPK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPM1	ENST00000371588.10	TSL:1 MANE Select	c.455G>T	p.Gly152Val	missense	Exon 6 of 9	ENSP00000360644.5	O60762
	DPM1	ENST00000371582.8	TSL:1	c.455G>T	p.Gly152Val	missense	Exon 6 of 10	ENSP00000360638.4	Q5QPK2
	DPM1	ENST00000466152.5	TSL:1	n.455G>T		non_coding_transcript_exon	Exon 6 of 9	ENSP00000507119.1	A0A804HIK9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251472 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Congenital disorder of glycosylation type 1E (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.61		Loss of ubiquitination at K149 (P = 0.05)
MVP		0.80
MPC		1.0
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.79
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777116; hg19: chr20-49558607;