11-78112745-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_024079.5(ALG8):c.803G>A(p.Arg268Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,666 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 25 hom., cov: 32)

Exomes 𝑓: 0.019 ( 305 hom. )

Consequence

ALG8
NM_024079.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.33

Publications

13 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.017484665).

BP6

Variant 11-78112745-C-T is Benign according to our data. Variant chr11-78112745-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96093.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 = 0.0142 (2153/152146) while in subpopulation NFE AF = 0.0215 (1459/68000). AF 95% confidence interval is 0.0205. There are 25 homozygotes in GnomAd4. There are 972 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG8	NM_024079.5 link	c.803G>A	p.Arg268Gln	missense_variant	Exon 8 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.803G>A	p.Arg268Gln	missense_variant	Exon 8 of 13	1	NM_024079.5	ENSP00000299626.5		Q9BVK2-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2153

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.00863

GnomAD2 exomes

AF:

0.0140

AC:

3514

AN:

250846

AF XY:

0.0139

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.00634

Gnomad ASJ exome

AF:

0.0344

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.0194

AC:

28408

AN:

1461520

Hom.:

305

Cov.:

AF XY:

0.0189

AC XY:

13767

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.00323

AC:

108

AN:

33472

American (AMR)

AF:

0.00696

AC:

311

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0359

AC:

939

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.00237

AC:

204

AN:

86216

European-Finnish (FIN)

AF:

0.0157

AC:

837

AN:

53372

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0225

AC:

24973

AN:

1111792

Other (OTH)

AF:

0.0170

AC:

1029

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1478

2956

4435

5913

7391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

938

1876

2814

3752

4690

<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:

0.0142

AC:

2153

AN:

152146

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

972

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00486

AC:

202

AN:

41532

American (AMR)

AF:

0.0100

AC:

153

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

122

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00270

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0176

AC:

186

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0215

AC:

1459

AN:

68000

Other (OTH)

AF:

0.00854

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0194

Hom.:

125

Bravo

AF:

0.0131

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0226

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0220

AC:

189

ExAC

AF:

0.0137

AC:

1661

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0195

EpiControl

AF:

0.0186

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 21, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 14, 2015

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28820871, 30061496) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALG8: BS1, BS2 -

ALG8 congenital disorder of glycosylation

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 28, 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

0.23

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;D;D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D;D;D;D

MetaRNN

Benign

0.017

T;T;T;T;T;T

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.4

M;M;M;.;.;.

PhyloP100

7.3

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.8

D;D;.;D;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;.;.

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.56

MPC

0.68

ClinPred

0.068

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.82

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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