rs1555570093

Positions:

• chr17-7586699-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_004870.4(MPDU1):​c.310G>A​(p.Gly104Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MPDU1 NM_004870.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.51

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 17-7586699-G-A is Pathogenic according to our data. Variant chr17-7586699-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495318.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDU1	NM_004870.4	c.310G>A	p.Gly104Ser	missense_variant	4/7	ENST00000250124.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDU1	ENST00000250124.11	c.310G>A	p.Gly104Ser	missense_variant	4/7	1	NM_004870.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T;.;T;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	D;D;.;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.79
MutPred		0.79		Gain of catalytic residue at S101 (P = 0.2103);Gain of catalytic residue at S101 (P = 0.2103);Gain of catalytic residue at S101 (P = 0.2103);.;.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.82

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: rs1555570093; hg19: chr17-7490017;