chr17-7586766-A-C

Variant names:

• chr17-7586766-A-C
• rs1555570110
• NM_004870.4:c.377A>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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
• Publications: 0 publications found

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]

MPDU1 Gene-Disease associations (from GenCC):

• MPDU1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004870.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDU1	NM_004870.4	MANE Select	c.377A>C	p.Gln126Pro	missense	Exon 4 of 7	NP_004861.2
	MPDU1	NM_001330073.1		c.377A>C	p.Gln126Pro	missense	Exon 4 of 6	NP_001317002.1
	MPDU1	NR_024603.1		n.588A>C		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDU1	ENST00000250124.11	TSL:1 MANE Select	c.377A>C	p.Gln126Pro	missense	Exon 4 of 7	ENSP00000250124.6
	MPDU1	ENST00000571877.1	TSL:1	n.298A>C		non_coding_transcript_exon	Exon 1 of 2
	MPDU1	ENST00000579445.5	TSL:3	c.377A>C	p.Gln126Pro	missense	Exon 4 of 6	ENSP00000464158.1

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

Jul 15, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.0032
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.42
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.43
MutPred		0.42		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
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555570110; hg19: chr17-7490084;