1-20654614-C-G

Variant names:

• chr1-20654614-C-G
• rs867045420
• NM_005216.5:c.645G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_005216.5(DDOST):​c.645G>C​(p.Gln215His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000782 in 1,407,544 control chromosomes in the GnomAD database, including 1 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000078 (1 hom.)
• Consequence: DDOST NM_005216.5 missense, splice_region
• Scores: Splicing: ADA: 0.9968
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.99
• Publications: 0 publications found

Genes affected

DDOST (HGNC:2728): (dolichyl-diphosphooligosaccharide--protein glycosyltransferase non-catalytic subunit) This gene encodes a component of the oligosaccharyltransferase complex which catalyzes the transfer of high-mannose oligosaccharides to asparagine residues on nascent polypeptides in the lumen of the rough endoplasmic reticulum. The protein complex co-purifies with ribosomes. The product of this gene is also implicated in the processing of advanced glycation endproducts (AGEs), which form from non-enzymatic reactions between sugars and proteins or lipids and are associated with aging and hyperglycemia. [provided by RefSeq, Jul 2008]

DDOST Gene-Disease associations (from GenCC):

• DDOST-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 1-20654614-C-G is Pathogenic according to our data. Variant chr1-20654614-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522968.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
DDOST	NM_005216.5	c.645G>C	p.Gln215His	missense_variant, splice_region_variant	Exon 6 of 11	ENST00000602624.7	NP_005207.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDOST	ENST00000602624.7	c.645G>C	p.Gln215His	missense_variant, splice_region_variant	Exon 6 of 11	1	NM_005216.5	ENSP00000473655.2
DDOST	ENST00000415136.6	c.696G>C	p.Gln232His	missense_variant, splice_region_variant	Exon 6 of 11	1		ENSP00000399457.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 171066 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000782 AC: 11 AN: 1407544 Hom.: 1 Cov.: 31 AF XY: 0.00000719 AC XY: 5 AN XY: 695056

African (AFR) AF: 0.00 AC: 0 AN: 32128

American (AMR) AF: 0.00 AC: 0 AN: 37024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25298

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36824

South Asian (SAS) AF: 0.0000501 AC: 4 AN: 79882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000554 AC: 6 AN: 1082348

Other (OTH) AF: 0.00 AC: 0 AN: 58402

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital disorder of glycosylation type Ir Pathogenic:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Palindrome, Gene Kavoshgaran Aria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;T;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.055	D
MutationAssessor	Uncertain	2.2	M;.;M
PhyloP100		4.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	.;.;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.011	.;.;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.82	P;.;P
Vest4		0.62
MutPred		0.42		Gain of catalytic residue at I230 (P = 0.0887);.;Gain of catalytic residue at I230 (P = 0.0887);
MVP		0.86
MPC		0.65
ClinPred		0.83	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.72
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 0

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

Other links and lift over

dbSNP: rs867045420; hg19: chr1-20981107;