rs17825668

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024079.5(ALG8):c.1316T>C(p.Ile439Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,505,436 control chromosomes in the GnomAD database, including 708 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 46 hom., cov: 33)

Exomes 𝑓: 0.029 ( 662 hom. )

Consequence

ALG8
NM_024079.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.57

Publications

15 publications found

Variant links:

Genes affected

ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ALG8 Gene-Disease associations (from GenCC):

ALG8-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
polycystic liver disease 3 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ALG8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00791803).

BP6

Variant 11-78104013-A-G is Benign according to our data. Variant chr11-78104013-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0213 (3243/152252) while in subpopulation NFE AF = 0.0334 (2274/67990). AF 95% confidence interval is 0.0323. There are 46 homozygotes in GnomAd4. There are 1511 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 46 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG8	NM_024079.5 link	c.1316T>C	p.Ile439Thr	missense_variant	Exon 12 of 13	ENST00000299626.10	NP_076984.2	Q9BVK2-1A0A024R5K5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG8	ENST00000299626.10 link	c.1316T>C	p.Ile439Thr	missense_variant	Exon 12 of 13	1	NM_024079.5	ENSP00000299626.5		Q9BVK2-1

Frequencies

GnomAD3 genomes

AF:

0.0213

AC:

3245

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00536

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.0374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00953

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0225

AC:

5505

AN:

245044

AF XY:

0.0233

show subpopulations

Gnomad AFR exome

AF:

0.00425

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0348

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0344

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0292

AC:

39464

AN:

1353184

Hom.:

662

Cov.:

AF XY:

0.0287

AC XY:

19463

AN XY:

677500

show subpopulations

African (AFR)

AF:

0.00630

AC:

197

AN:

31284

American (AMR)

AF:

0.0171

AC:

748

AN:

43630

Ashkenazi Jewish (ASJ)

AF:

0.0358

AC:

898

AN:

25104

East Asian (EAS)

AF:

0.0000513

AC:

AN:

38978

South Asian (SAS)

AF:

0.0111

AC:

913

AN:

82450

European-Finnish (FIN)

AF:

0.0133

AC:

704

AN:

52826

Middle Eastern (MID)

AF:

0.0333

AC:

185

AN:

5558

European-Non Finnish (NFE)

AF:

0.0336

AC:

34156

AN:

1016772

Other (OTH)

AF:

0.0294

AC:

1661

AN:

56582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

1503

3006

4509

6012

7515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1194

2388

3582

4776

5970

<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:

0.0213

AC:

3243

AN:

152252

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1511

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00534

AC:

222

AN:

41562

American (AMR)

AF:

0.0219

AC:

335

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0374

AC:

130

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00933

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0109

AC:

116

AN:

10610

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0334

AC:

2274

AN:

67990

Other (OTH)

AF:

0.0241

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0303

Hom.:

384

Bravo

AF:

0.0222

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0314

AC:

121

ESP6500AA

AF:

0.00485

AC:

ESP6500EA

AF:

0.0366

AC:

311

ExAC

AF:

0.0217

AC:

2628

Asia WGS

AF:

0.00579

AC:

AN:

3470

EpiCase

AF:

0.0398

EpiControl

AF:

0.0408

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 30, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALG8 congenital disorder of glycosylation

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

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

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.;.

Eigen

Benign

-0.045

Eigen_PC

Benign

-0.028

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.67

T;T;.;T

MetaRNN

Benign

0.0079

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.;L;L

PhyloP100

2.6

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

N;N;N;.

REVEL

Benign

0.27

Sift

Benign

0.039

D;D;D;.

Sift4G

Uncertain

0.050

T;D;D;D

Polyphen

0.083

B;.;.;.

Vest4

0.098

MPC

0.19

ClinPred

0.021

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.31

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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