rs665278

chr11-78114274-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.542

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]

ACMG classification

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	UniProt
ALG8	NM_024079.5	c.665A>G	p.Asn222Ser	missense_variant	6/13	ENST00000299626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG8	ENST00000299626.10	c.665A>G	p.Asn222Ser	missense_variant	6/13	1	NM_024079.5	P3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27115 AN: 152124 Hom.: 2909 Cov.: 33

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

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.: 39 AF XY: 0.221 AC XY: 160373 AN XY: 727118

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.: 33 AF XY: 0.178 AC XY: 13213 AN XY: 74420

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:9

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

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	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	11
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	D
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	T
MutationAssessor	Benign	-0.58	N;N;N;.;.;.;.;.
MutationTaster	Benign	0.77	P;P
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs665278; hg19: chr11-77825320; COSMIC: COSV55199658; COSMIC: COSV55199658;