rs60224379

chr20-50935243-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003859.3(DPM1):c.679-7A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,376,748 control chromosomes in the GnomAD database, including 4,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (2136 hom., cov: 29)
  • Exomes 𝑓: 0.027 (1922 hom.)
• Consequence: DPM1 NM_003859.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002757
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0770

Genes affected

DPM1 (HGNC:3005): (dolichyl-phosphate mannosyltransferase subunit 1, catalytic) Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. Human DPM1 lacks a carboxy-terminal transmembrane domain and signal sequence and is regulated by DPM2. Mutations in this gene are associated with congenital disorder of glycosylation type Ie. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

ADNP-AS1 (HGNC:51227): (ADNP antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-50935243-T-A is Benign according to our data. Variant chr20-50935243-T-A is described in ClinVar as [Benign]. Clinvar id is 94380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-50935243-T-A is described in Lovd as [Benign]. Variant chr20-50935243-T-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPM1	NM_003859.3	c.679-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371588.10
ADNP-AS1	NR_110008.1	n.149+3794T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPM1	ENST00000371588.10	c.679-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003859.3	P1
ADNP-AS1	ENST00000558899.2	n.149+3794T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15399 AN: 148044 Hom.: 2123 Cov.: 29

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0839

GnomAD4 exome AF: 0.0267 AC: 32822 AN: 1228624 Hom.: 1922 Cov.: 21 AF XY: 0.0256 AC XY: 15824 AN XY: 616974

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.0337

Gnomad4 ASJ exome AF: 0.0486

Gnomad4 EAS exome AF: 0.0209

Gnomad4 SAS exome AF: 0.0299

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0446

GnomAD4 genome AF: 0.104 AC: 15437 AN: 148124 Hom.: 2136 Cov.: 29 AF XY: 0.101 AC XY: 7312 AN XY: 72054

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.0474

Gnomad4 ASJ AF: 0.0455

Gnomad4 EAS AF: 0.0261

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0837

Alfa AF: 0.0462 Hom.: 168

Bravo AF: 0.114

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Congenital disorder of glycosylation type 1E Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.6
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.046
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: rs60224379; hg19: chr20-49551780;