chr1-155140057-C-G

Position:

• chr1-155140057-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_153741.2(DPM3):​c.184G>C​(p.Ala62Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A62V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DPM3 NM_153741.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Dolichol-phosphate mannosyltransferase subunit 3 (size 91) in uniprot entity DPM3_HUMAN there are 8 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, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPM3	NM_153741.2	c.184G>C	p.Ala62Pro	missense_variant	2/2	ENST00000368400.5
DPM3	NM_018973.4	c.274G>C	p.Ala92Pro	missense_variant	1/1
DPM3	XM_017001498.2	c.184G>C	p.Ala62Pro	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPM3	ENST00000368400.5	c.184G>C	p.Ala62Pro	missense_variant	2/2	1	NM_153741.2	P1
DPM3	ENST00000368399.1	c.274G>C	p.Ala92Pro	missense_variant	1/1
DPM3	ENST00000341298.3	c.184G>C	p.Ala62Pro	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DPM3-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2021

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DPM3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 62 of the DPM3 protein (p.Ala62Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.040	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.75
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.069	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.90
MutPred		0.63		.;Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.91
MPC		1.1
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155112533;