chr1-20654614-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005216.5(DDOST):​c.645G>T​(p.Gln215His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DDOST NM_005216.5 missense, splice_region
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407544 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
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	0.12	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.055	D
MutationAssessor	Uncertain	2.2	M;.;M
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		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.46		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs867045420; hg19: chr1-20981107;