chr1-155140048-G-A

Variant names:

• chr1-155140048-G-A
• rs1054576178
• NM_153741.2:c.193C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_153741.2(DPM3):​c.193C>T​(p.His65Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. H65R) 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: 4.88

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPM3	NM_153741.2	c.193C>T	p.His65Tyr	missense_variant	Exon 2 of 2	ENST00000368400.5	NP_714963.1
DPM3	NM_018973.4	c.283C>T	p.His95Tyr	missense_variant	Exon 1 of 1		NP_061846.2
DPM3	XM_017001498.2	c.193C>T	p.His65Tyr	missense_variant	Exon 2 of 2		XP_016856987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPM3	ENST00000368400.5	c.193C>T	p.His65Tyr	missense_variant	Exon 2 of 2	1	NM_153741.2	ENSP00000357385.5
DPM3	ENST00000368399.1	c.283C>T	p.His95Tyr	missense_variant	Exon 1 of 1	6		ENSP00000357384.1
DPM3	ENST00000341298.3	c.193C>T	p.His65Tyr	missense_variant	Exon 2 of 2	2		ENSP00000344338.3

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

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with DPM3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 65 of the DPM3 protein (p.His65Tyr). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.47	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.87	.;P;P
Vest4		0.39
MutPred		0.54		.;Loss of disorder (P = 0.0597);Loss of disorder (P = 0.0597);
MVP		0.86
MPC		0.87
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.81
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs1054576178; hg19: chr1-155112524;