chr1-20654241-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The NM_005216.5(DDOST):c.776C>T(p.Ala259Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,550,972 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 17 hom. )

Consequence

DDOST
NM_005216.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.64

Publications

5 publications found

Variant links:

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

DDOST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-20654241-G-A is Benign according to our data. Variant chr1-20654241-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 295135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20654241-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 295135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20654241-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 295135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDOST	NM_005216.5 link	c.776C>T	p.Ala259Val	missense_variant	Exon 7 of 11	ENST00000602624.7	NP_005207.3	P39656A0A024RAD5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDOST	ENST00000602624.7 link	c.776C>T	p.Ala259Val	missense_variant	Exon 7 of 11	1	NM_005216.5	ENSP00000473655.2		A0A0C4DGS1
DDOST	ENST00000415136.6 link	c.827C>T	p.Ala276Val	missense_variant	Exon 7 of 11	1		ENSP00000399457.3		P39656-1

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00750

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00247

AC:

386

AN:

156400

AF XY:

0.00242

show subpopulations

Gnomad AFR exome

AF:

0.000115

Gnomad AMR exome

AF:

0.0000808

Gnomad ASJ exome

AF:

0.000703

Gnomad EAS exome

AF:

0.00635

Gnomad FIN exome

AF:

0.0138

Gnomad NFE exome

AF:

0.000959

Gnomad OTH exome

AF:

0.00113

GnomAD4 exome

AF:

0.00154

AC:

2153

AN:

1398648

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1087

AN XY:

689840

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31576

American (AMR)

AF:

0.000112

AC:

AN:

35710

Ashkenazi Jewish (ASJ)

AF:

0.000715

AC:

AN:

25178

East Asian (EAS)

AF:

0.0121

AC:

432

AN:

35760

South Asian (SAS)

AF:

0.00126

AC:

100

AN:

79212

European-Finnish (FIN)

AF:

0.0132

AC:

651

AN:

49292

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5030

European-Non Finnish (NFE)

AF:

0.000792

AC:

855

AN:

1078968

Other (OTH)

AF:

0.00145

AC:

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152324

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00752

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0141

AC:

150

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00153

AC:

104

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000846

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000615

AC:

ExAC

AF:

0.00129

AC:

112

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 16, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital disorder of glycosylation type Ir

Benign:1

Dec 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;.

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.6

L;.;L

PhyloP100

7.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.2

.;.;N

REVEL

Uncertain

0.40

Sift

Benign

0.14

.;.;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.38

B;.;B

Vest4

0.55

MVP

0.84

MPC

0.22

ClinPred

0.026

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.24

gMVP

0.62

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.53

Position offset: 2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over