rs199911532

Positions:

• chr11-78127442-C-G
• chr11-78127442-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_024079.5(ALG8):​c.96-6G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,611,630 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: ALG8 NM_024079.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005400
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0160

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 -9 ACMG points.

• BP6: Variant 11-78127442-C-G is Benign according to our data. Variant chr11-78127442-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218479.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr11-78127442-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0011 (1602/1459450) while in subpopulation MID AF= 0.0142 (82/5758). AF 95% confidence interval is 0.0118. There are 8 homozygotes in gnomad4_exome. There are 815 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG8	NM_024079.5	c.96-6G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000299626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG8	ENST00000299626.10	c.96-6G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024079.5	P3

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152064 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00160 AC: 402 AN: 250928 Hom.: 2 AF XY: 0.00163 AC XY: 221 AN XY: 135680

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00110 AC: 1602 AN: 1459450 Hom.: 8 Cov.: 31 AF XY: 0.00112 AC XY: 815 AN XY: 726228

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000734

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152180 Hom.: 1 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74388

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00130

EpiCase AF: 0.00164

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ALG8 congenital disorder of glycosylation Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 11, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

ALG8: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	19
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199911532; hg19: chr11-77838488;