rs772047932

chr17-7583872-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004870.4(MPDU1):c.10G>A(p.Glu4Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E4E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MPDU1 NM_004870.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

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-AS1 (HGNC:40379): (MPDU1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41885367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDU1	NM_004870.4	c.10G>A	p.Glu4Lys	missense_variant	1/7	ENST00000250124.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDU1	ENST00000250124.11	c.10G>A	p.Glu4Lys	missense_variant	1/7	1	NM_004870.4	P1
MPDU1-AS1	ENST00000655859.2	n.181+46C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250768 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MPDU1-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 23, 2018

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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MPDU1-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces glutamic acid with lysine at codon 4 of the MPDU1 protein (p.Glu4Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	22
Dann	Pathogenic	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationTaster	Benign	0.88	D;D;D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.96	.;D;.;.;.;.
Vest4		0.34
MutPred		0.17		Gain of ubiquitination at E4 (P = 0.0325);Gain of ubiquitination at E4 (P = 0.0325);Gain of ubiquitination at E4 (P = 0.0325);Gain of ubiquitination at E4 (P = 0.0325);Gain of ubiquitination at E4 (P = 0.0325);Gain of ubiquitination at E4 (P = 0.0325);
MVP		0.86
MPC		0.40
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.46
gMVP		0.79

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: rs772047932; hg19: chr17-7487190;