17-7587859-G-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 325524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7587859-G-T is described in Lovd as [Likely_benign].
• 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

GnomAD3 exomes AF: 0.715 AC: 95351 AN: 133404 Hom.: 34638 AF XY: 0.729 AC XY: 53077 AN XY: 72768

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 SAS exome AF: 0.834

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

Gnomad4 AFR exome AF: 0.575

Gnomad4 AMR exome AF: 0.567

Gnomad4 ASJ exome AF: 0.794

Gnomad4 EAS exome AF: 0.804

Gnomad4 SAS exome AF: 0.832

Gnomad4 FIN exome AF: 0.690

Gnomad4 NFE exome AF: 0.726

Gnomad4 OTH exome AF: 0.724

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

Gnomad4 AFR AF: 0.576

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.793

Gnomad4 EAS AF: 0.773

Gnomad4 SAS AF: 0.836

Gnomad4 FIN AF: 0.696

Gnomad4 NFE AF: 0.726

Gnomad4 OTH AF: 0.682

Alfa AF: 0.727 Hom.: 86407

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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