17-7587859-G-T

Variant names:

• chr17-7587859-G-T
• rs4227
• NM_004870.4:c.*308G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004870.4(MPDU1):​c.*308G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 520,342 control chromosomes in the GnomAD database, including 134,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35439 hom., cov: 32)
  • Exomes 𝑓: 0.73 (99355 hom.)
• Consequence: MPDU1 NM_004870.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.325
• Publications: 66 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-7587859-G-T is Benign according to our data. Variant chr17-7587859-G-T is described in ClinVar as Benign. ClinVar VariationId is 325524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDU1	NM_004870.4	c.*308G>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000250124.11	NP_004861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPDU1	ENST00000250124.11	c.*308G>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_004870.4	ENSP00000250124.6

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103073 AN: 151902 Hom.: 35419 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.691

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.835

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.680

GnomAD2 exomes AF: 0.715 AC: 95351 AN: 133404 AF XY: 0.729

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.564

Gnomad ASJ exome AF: 0.795

Gnomad EAS exome AF: 0.774

Gnomad FIN exome AF: 0.689

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.740

GnomAD4 exome AF: 0.730 AC: 268921 AN: 368322 Hom.: 99355 Cov.: 2 AF XY: 0.742 AC XY: 152388 AN XY: 205490

African (AFR) AF: 0.575 AC: 6358 AN: 11054

American (AMR) AF: 0.567 AC: 16544 AN: 29182

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 10771 AN: 13572

East Asian (EAS) AF: 0.804 AC: 11828 AN: 14714

South Asian (SAS) AF: 0.832 AC: 50140 AN: 60274

European-Finnish (FIN) AF: 0.690 AC: 11450 AN: 16588

Middle Eastern (MID) AF: 0.789 AC: 1253 AN: 1588

European-Non Finnish (NFE) AF: 0.726 AC: 147108 AN: 202748

Other (OTH) AF: 0.724 AC: 13469 AN: 18602

GnomAD4 genome AF: 0.678 AC: 103130 AN: 152020 Hom.: 35439 Cov.: 32 AF XY: 0.682 AC XY: 50651 AN XY: 74316

African (AFR) AF: 0.576 AC: 23856 AN: 41440

American (AMR) AF: 0.623 AC: 9508 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 2750 AN: 3468

East Asian (EAS) AF: 0.773 AC: 3992 AN: 5164

South Asian (SAS) AF: 0.836 AC: 4036 AN: 4826

European-Finnish (FIN) AF: 0.696 AC: 7358 AN: 10578

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49353 AN: 67962

Other (OTH) AF: 0.682 AC: 1435 AN: 2104

Alfa AF: 0.718 Hom.: 173337

Bravo AF: 0.666

Asia WGS AF: 0.773 AC: 2686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MPDU1-congenital disorder of glycosylation Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.80
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs4227; hg19: chr17-7491177; COSMIC: COSV51469439; COSMIC: COSV51469439;