rs1555570110

Positions:

• chr17-7586766-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_004870.4(MPDU1):​c.377A>C​(p.Gln126Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MPDU1 NM_004870.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.20

Genes affected

MPDU1 (HGNC:7207): (mannose-P-dolichol utilization defect 1) This gene encodes an endoplasmic reticulum membrane protein that is required for utilization of the mannose donor mannose-P-dolichol in the synthesis of lipid-linked oligosaccharides and glycosylphosphatidylinositols. Mutations in this gene result in congenital disorder of glycosylation type If. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7586766-A-C is Pathogenic according to our data. Variant chr17-7586766-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495319.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30080926). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPDU1	NM_004870.4	c.377A>C	p.Gln126Pro	missense_variant	4/7	ENST00000250124.11	NP_004861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPDU1	ENST00000250124.11	c.377A>C	p.Gln126Pro	missense_variant	4/7	1	NM_004870.4	ENSP00000250124	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

MPDU1-congenital disorder of glycosylation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences

Jul 15, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.0047	T;.;T;.
Eigen	Benign	-0.0032
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.48	T;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	0.74	D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;N;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.26	T;T;.;.
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.43
MutPred		0.42		Gain of glycosylation at T127 (P = 0.0771);Gain of glycosylation at T127 (P = 0.0771);Gain of glycosylation at T127 (P = 0.0771);.;
MVP		0.89
MPC		0.44
ClinPred		0.52	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.75

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: rs1555570110; hg19: chr17-7490084;