NM_024079.5:c.96-6G>C

Variant names:

• chr11-78127442-C-G
• rs199911532
• NM_024079.5:c.96-6G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_024079.5(ALG8):​c.96-6G>C variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00005400
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0160
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 218479.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 815 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024079.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG8	NM_024079.5	MANE Select	c.96-6G>C		splice_region intron	N/A	NP_076984.2
	ALG8	NM_001425224.1		c.96-6G>C		splice_region intron	N/A	NP_001412153.1
	ALG8	NM_001425225.1		c.96-6G>C		splice_region intron	N/A	NP_001412154.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG8	ENST00000299626.10	TSL:1 MANE Select	c.96-6G>C		splice_region intron	N/A	ENSP00000299626.5
	ALG8	ENST00000532050.5	TSL:1	n.96-6G>C		splice_region intron	N/A	ENSP00000437199.1
	ALG8	ENST00000524925.2	TSL:3	n.206G>C		non_coding_transcript_exon	Exon 1 of 12

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

GnomAD2 exomes AF: 0.00160 AC: 402 AN: 250928 AF XY: 0.00163

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 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

African (AFR) AF: 0.000479 AC: 16 AN: 33428

American (AMR) AF: 0.000894 AC: 40 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 431 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.000870 AC: 75 AN: 86182

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53346

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5758

European-Non Finnish (NFE) AF: 0.000734 AC: 815 AN: 1109942

Other (OTH) AF: 0.00234 AC: 141 AN: 60310

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

African (AFR) AF: 0.000289 AC: 12 AN: 41538

American (AMR) AF: 0.00157 AC: 24 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00130

EpiCase AF: 0.00164

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	ALG8 congenital disorder of glycosylation (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	19
DANN	Benign	0.50
PhyloP100		-0.016
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs199911532; hg19: chr11-77838488;