chr20-50935242-T-TAA

Position:

• chr20-50935242-T-TAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003859.3(DPM1):​c.679-7_679-6insTT 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 0.00337 in 1,543,996 control chromosomes in the GnomAD database, including 95 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (82 hom., cov: 29)
  • Exomes 𝑓: 0.0018 (13 hom.)
• Consequence: DPM1 NM_003859.3 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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 -16 ACMG points.

• BP6: Variant 20-50935242-T-TAA is Benign according to our data. Variant chr20-50935242-T-TAA is described in ClinVar as [Likely_benign]. Clinvar id is 235463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPM1	NM_003859.3	c.679-7_679-6insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371588.10
ADNP-AS1	NR_110008.1	n.149+3793_149+3794insAA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPM1	ENST00000371588.10	c.679-7_679-6insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003859.3	P1
ADNP-AS1	ENST00000558899.2	n.149+3793_149+3794insAA		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 2676 AN: 124312 Hom.: 79 Cov.: 29

Gnomad AFR AF: 0.0900

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0144

Gnomad NFE AF: 0.000301

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00355 AC: 835 AN: 235258 Hom.: 2 AF XY: 0.00249 AC XY: 319 AN XY: 128104

Gnomad AFR exome AF: 0.0549

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000745

Gnomad EAS exome AF: 0.000288

Gnomad SAS exome AF: 0.000177

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00177 AC: 2515 AN: 1419624 Hom.: 13 Cov.: 21 AF XY: 0.00151 AC XY: 1071 AN XY: 708782

Gnomad4 AFR exome AF: 0.0609

Gnomad4 AMR exome AF: 0.00272

Gnomad4 ASJ exome AF: 0.000429

Gnomad4 EAS exome AF: 0.000229

Gnomad4 SAS exome AF: 0.000320

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000262

Gnomad4 OTH exome AF: 0.00337

GnomAD4 genome AF: 0.0216 AC: 2684 AN: 124372 Hom.: 82 Cov.: 29 AF XY: 0.0208 AC XY: 1264 AN XY: 60738

Gnomad4 AFR AF: 0.0901

Gnomad4 AMR AF: 0.00722

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000301

Gnomad4 OTH AF: 0.0136

Alfa AF: 0.000830 Hom.: 2

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	- -

Congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital disorder of glycosylation type 1E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

DPM1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11480415; hg19: chr20-49551779;