11-78114274-T-C

Position:

chr11-78114274-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024079.5(ALG8):c.665A>G(p.Asn222Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,832 control chromosomes in the GnomAD database, including 39,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2910 hom., cov: 33)

Exomes 𝑓: 0.22 ( 36573 hom. )

Consequence

ALG8
NM_024079.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.542

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:

ALG8 (HGNC:):

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=0.0013854206).

BP6

Variant 11-78114274-T-C is Benign according to our data. Variant chr11-78114274-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 96092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-78114274-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG8	NM_024079.5 linkuse as main transcript	c.665A>G	p.Asn222Ser	missense_variant	6/13	ENST00000299626.10	NP_076984.2	Q9BVK2-1A0A024R5K5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG8	ENST00000299626.10 linkuse as main transcript	c.665A>G	p.Asn222Ser	missense_variant	6/13	1	NM_024079.5	ENSP00000299626.5		Q9BVK2-1

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27115

AN:

152124

Hom.:

2909

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0620

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.0927

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.197

GnomAD3 exomes

AF:

0.202

AC:

50661

AN:

250942

Hom.:

5531

AF XY:

0.206

AC XY:

27991

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.0602

Gnomad AMR exome

AF:

0.213

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.100

Gnomad SAS exome

AF:

0.209

Gnomad FIN exome

AF:

0.180

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.220

AC:

321515

AN:

1461590

Hom.:

36573

Cov.:

AF XY:

0.221

AC XY:

160373

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0585

Gnomad4 AMR exome

AF:

0.216

Gnomad4 ASJ exome

AF:

0.305

Gnomad4 EAS exome

AF:

0.0839

Gnomad4 SAS exome

AF:

0.206

Gnomad4 FIN exome

AF:

0.184

Gnomad4 NFE exome

AF:

0.231

Gnomad4 OTH exome

AF:

0.214

GnomAD4 genome

AF:

0.178

AC:

27122

AN:

152242

Hom.:

2910

Cov.:

AF XY:

0.178

AC XY:

13213

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0618

Gnomad4 AMR

AF:

0.232

Gnomad4 ASJ

AF:

0.300

Gnomad4 EAS

AF:

0.0933

Gnomad4 SAS

AF:

0.207

Gnomad4 FIN

AF:

0.191

Gnomad4 NFE

AF:

0.233

Gnomad4 OTH

AF:

0.195

Alfa

AF:

0.223

Hom.:

9925

Bravo

AF:

0.175

TwinsUK

AF:

0.228

AC:

846

ALSPAC

AF:

0.246

AC:

948

ESP6500AA

AF:

0.0739

AC:

325

ESP6500EA

AF:

0.229

AC:

1967

ExAC

AF:

0.199

AC:

24110

Asia WGS

AF:

0.139

AC:

482

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG8 congenital disorder of glycosylation

Benign:5

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Congenital disorder of glycosylation, type Ih, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.33

DEOGEN2

Benign

0.11

T;.;.;T;T;.;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;.;D;D;D;D;D;T

MetaRNN

Benign

0.0014

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.58

N;N;N;.;.;.;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.42

N;N;.;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.85

T;T;.;T;T;T;T;T

Sift4G

Benign

0.65

T;T;T;.;.;.;.;.

Polyphen

0.0

B;.;.;.;.;.;.;.

Vest4

0.054

MPC

0.12

ClinPred

0.0056

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.081

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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