rs201975029

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM5BP4_Strong

The NM_019109.5(ALG1):c.827G>A(p.Arg276Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000772 in 1,611,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 0 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:2

Conservation

PhyloP100: 7.03

Publications

3 publications found

Variant links:

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 Gene-Disease associations (from GenCC):

ALG1-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ALG1 links:

ENSG00000260882 (HGNC:):

ENSG00000260882 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-5078842-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.06585652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5 link	c.827G>A	p.Arg276Gln	missense_variant	Exon 7 of 13	ENST00000262374.10	NP_061982.3	Q9BT22-1
ALG1	NM_001438123.1 link	c.827G>A	p.Arg276Gln	missense_variant	Exon 7 of 12		NP_001425052.1
ALG1	NM_001330504.2 link	c.494G>A	p.Arg165Gln	missense_variant	Exon 7 of 13		NP_001317433.1	Q9BT22-2
ALG1	XR_007064892.1 link	n.834G>A		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10 link	c.827G>A	p.Arg276Gln	missense_variant	Exon 7 of 13	1	NM_019109.5	ENSP00000262374.5		Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000651

AC:

162

AN:

248660

AF XY:

0.000659

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.000741

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000805

AC:

1175

AN:

1459596

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

596

AN XY:

726148

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33414

American (AMR)

AF:

0.0000447

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000917

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00216

AC:

115

AN:

53206

Middle Eastern (MID)

AF:

0.000228

AC:

AN:

4388

European-Non Finnish (NFE)

AF:

0.000841

AC:

935

AN:

1111734

Other (OTH)

AF:

0.000648

AC:

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

151

226

302

377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000453

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000520

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

ALG1-congenital disorder of glycosylation

Pathogenic:2Uncertain:1Benign:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 29, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Oct 30, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26931382, 20679665) -

ALG1-related disorder

Benign:1

Jun 16, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

.;D;D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

.;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.066

T;T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.3

.;M;.;.

PhyloP100

7.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.7

.;D;.;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

.;D;.;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.69

MVP

0.94

MPC

0.27

ClinPred

0.28

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.76

gMVP

0.86

Mutation Taster

=51/49

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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