rs1185483085

Variant names:

• chr11-119100730-G-GGCAGCTGTAGGTAGCA
• rs1185483085
• NM_001382.4:c.380_395dupTGCTACCTACAGCTGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001382.4(DPAGT1):​c.380_395dupTGCTACCTACAGCTGC​(p.Ser133AlafsTer64) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A132A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DPAGT1 NM_001382.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

DPAGT1 (HGNC:2995): (dolichyl-phosphate N-acetylglucosaminephosphotransferase 1) The protein encoded by this gene is an enzyme that catalyzes the first step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis. This enzyme belongs to the glycosyltransferase family 4. This protein is an integral membrane protein of the endoplasmic reticulum. The congenital disorder of glycosylation type Ij is caused by mutation in the gene encoding this enzyme. [provided by RefSeq, Jul 2008]

DPAGT1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• DPAGT1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-119100730-G-GGCAGCTGTAGGTAGCA is Pathogenic according to our data. Variant chr11-119100730-G-GGCAGCTGTAGGTAGCA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPAGT1	NM_001382.4	c.380_395dupTGCTACCTACAGCTGC	p.Ser133AlafsTer64	frameshift_variant	Exon 3 of 9	ENST00000354202.9	NP_001373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPAGT1	ENST00000354202.9	c.380_395dupTGCTACCTACAGCTGC	p.Ser133AlafsTer64	frameshift_variant	Exon 3 of 9	1	NM_001382.4	ENSP00000346142.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251388 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DPAGT1-congenital disorder of glycosylation;C3553645:Congenital myasthenic syndrome 13 Pathogenic:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser133Alafs*64) in the DPAGT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DPAGT1 are known to be pathogenic (PMID: 22742743). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of DPAGT1-congenital disorder of glycosylation (PMID: 30117111). ClinVar contains an entry for this variant (Variation ID: 521720). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Apr 20, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital disorder of glycosylation Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Mar 26, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with congenital disorder of glycosylation who had a second a pathogenic variant DPAGT1, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (PMID: 30117111); Observed with a second DPAGT1 variant in trans in an individual with childhood onset limb-girdle weakness (PMID: 38124360); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30117111, 33340551, 37766827, 38124360) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1185483085; hg19: chr11-118971440;