rs17825668

Positions:

chr11-78104013-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 166677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-78104013-A-G is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG8	NM_024079.5 linkuse as main transcript	c.1316T>C	p.Ile439Thr	missense_variant	12/13	ENST00000299626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG8	ENST00000299626.10 linkuse as main transcript	c.1316T>C	p.Ile439Thr	missense_variant	12/13	1	NM_024079.5	P3	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

GnomAD3 exomes

AF:

0.0225

AC:

5505

AN:

245044

Hom.:

AF XY:

0.0233

AC XY:

3092

AN XY:

132636

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 SAS exome

AF:

0.0101

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

Gnomad4 AFR exome

AF:

0.00630

Gnomad4 AMR exome

AF:

0.0171

Gnomad4 ASJ exome

AF:

0.0358

Gnomad4 EAS exome

AF:

0.0000513

Gnomad4 SAS exome

AF:

0.0111

Gnomad4 FIN exome

AF:

0.0133

Gnomad4 NFE exome

AF:

0.0336

Gnomad4 OTH exome

AF:

0.0294

GnomAD4 genome

AF:

0.0213

AC:

3243

AN:

152252

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1511

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00534

Gnomad4 AMR

AF:

0.0219

Gnomad4 ASJ

AF:

0.0374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00933

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.0334

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0321

Hom.:

211

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 19, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ALG8 congenital disorder of glycosylation

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

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

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

MutationTaster

Benign

1.0

N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over