rs74336587

Variant names:

• chr17-7586099-C-T
• rs74336587
• NM_004870.4:c.302+21C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004870.4(MPDU1):​c.302+21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,612,516 control chromosomes in the GnomAD database, including 595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (44 hom., cov: 31)
  • Exomes 𝑓: 0.026 (551 hom.)
• Consequence: MPDU1 NM_004870.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.162
• Publications: 2 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=-0.81).
• BP6: Variant 17-7586099-C-T is Benign according to our data. Variant chr17-7586099-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 259558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0185 (2810/152262) while in subpopulation NFE AF = 0.0277 (1886/68010). AF 95% confidence interval is 0.0267. There are 44 homozygotes in GnomAd4. There are 1339 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDU1	NM_004870.4	c.302+21C>T		intron_variant	Intron 3 of 6	ENST00000250124.11	NP_004861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPDU1	ENST00000250124.11	c.302+21C>T		intron_variant	Intron 3 of 6	1	NM_004870.4	ENSP00000250124.6

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2809 AN: 152144 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0223 AC: 5587 AN: 250732 AF XY: 0.0228

Gnomad AFR exome AF: 0.00469

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0247

GnomAD4 exome AF: 0.0257 AC: 37540 AN: 1460254 Hom.: 551 Cov.: 32 AF XY: 0.0259 AC XY: 18833 AN XY: 726452

African (AFR) AF: 0.00428 AC: 143 AN: 33434

American (AMR) AF: 0.0192 AC: 858 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 338 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0263 AC: 2271 AN: 86188

European-Finnish (FIN) AF: 0.0219 AC: 1167 AN: 53370

Middle Eastern (MID) AF: 0.0186 AC: 89 AN: 4784

European-Non Finnish (NFE) AF: 0.0282 AC: 31316 AN: 1111670

Other (OTH) AF: 0.0225 AC: 1358 AN: 60284

GnomAD4 genome AF: 0.0185 AC: 2810 AN: 152262 Hom.: 44 Cov.: 31 AF XY: 0.0180 AC XY: 1339 AN XY: 74452

African (AFR) AF: 0.00546 AC: 227 AN: 41556

American (AMR) AF: 0.0158 AC: 241 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4826

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0277 AC: 1886 AN: 68010

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.0234 Hom.: 41

Bravo AF: 0.0178

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 17, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.39
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs74336587; hg19: chr17-7489417;