17-7587492-G-C

Variant names:

• chr17-7587492-G-C
• rs10852891
• NM_004870.4:c.685G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004870.4(MPDU1):​c.685G>C​(p.Ala229Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A229T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MPDU1 NM_004870.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.903
• Publications: 38 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

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.685G>C	p.Ala229Pro	missense	Exon 7 of 7	NP_004861.2
	MPDU1	NR_024603.1		n.896G>C		non_coding_transcript_exon	Exon 7 of 7
	MPDU1	NM_001330073.1		c.*48G>C		3_prime_UTR	Exon 6 of 6	NP_001317002.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDU1	ENST00000250124.11	TSL:1 MANE Select	c.685G>C	p.Ala229Pro	missense	Exon 7 of 7	ENSP00000250124.6
	MPDU1	ENST00000571877.1	TSL:1	n.870G>C		non_coding_transcript_exon	Exon 2 of 2
	MPDU1	ENST00000359822.10	TSL:3	n.*436G>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000352876.6

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 4706

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.90
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.55
Sift	Benign	0.066	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.55
MutPred		0.63		Loss of helix (P = 0.079)
MVP		0.80
MPC		0.91
ClinPred		0.93	D
GERP RS		2.1
Varity_R		0.32
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10852891; hg19: chr17-7490810;