rs1057518905

Positions:

• chr1-155140104-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_153741.2(DPM3):​c.137T>A​(p.Leu46Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DPM3 NM_153741.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.04

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 8 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, 0.921
• PP5: Variant 1-155140104-A-T is Pathogenic according to our data. Variant chr1-155140104-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374109.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPM3	NM_153741.2	c.137T>A	p.Leu46Gln	missense_variant	2/2	ENST00000368400.5	NP_714963.1
DPM3	NM_018973.4	c.227T>A	p.Leu76Gln	missense_variant	1/1		NP_061846.2
DPM3	XM_017001498.2	c.137T>A	p.Leu46Gln	missense_variant	2/2		XP_016856987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPM3	ENST00000368400.5	c.137T>A	p.Leu46Gln	missense_variant	2/2	1	NM_153741.2	ENSP00000357385	P1
DPM3	ENST00000368399.1	c.227T>A	p.Leu76Gln	missense_variant	1/1			ENSP00000357384
DPM3	ENST00000341298.3	c.137T>A	p.Leu46Gln	missense_variant	2/2	2		ENSP00000344338	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy;C0878544:Cardiomyopathy;C4021726:EMG: myopathic abnormalities Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.98
MutPred		0.72		.;Gain of catalytic residue at L46 (P = 0.0047);Gain of catalytic residue at L46 (P = 0.0047);
MVP		0.96
MPC		0.98
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518905; hg19: chr1-155112580;