rs200068321

Variant names:

• chr11-78104044-T-C
• rs200068321
• NM_024079.5:c.1285A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024079.5(ALG8):​c.1285A>G​(p.Ile429Val) variant causes a missense change. The variant allele was found at a frequency of 0.000155 in 1,495,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ALG8 NM_024079.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.34
• Publications: 1 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):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• ALG8-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• polycystic liver disease 3 with or without kidney cysts

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17699343).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG8	NM_024079.5	MANE Select	c.1285A>G	p.Ile429Val	missense	Exon 12 of 13	NP_076984.2	A0A024R5K5
	ALG8	NM_001425224.1		c.1378A>G	p.Ile460Val	missense	Exon 13 of 14	NP_001412153.1
	ALG8	NM_001425225.1		c.1333A>G	p.Ile445Val	missense	Exon 13 of 14	NP_001412154.1	H0YDD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG8	ENST00000299626.10	TSL:1 MANE Select	c.1285A>G	p.Ile429Val	missense	Exon 12 of 13	ENSP00000299626.5	Q9BVK2-1
	ALG8	ENST00000679559.1		c.1285A>G	p.Ile429Val	missense	Exon 12 of 14	ENSP00000505433.1	A0A7P0T919
	ALG8	ENST00000532440.6	TSL:3	c.1333A>G	p.Ile445Val	missense	Exon 13 of 14	ENSP00000433429.2	H0YDD3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152076 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000235 AC: 57 AN: 243018 AF XY: 0.000236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000148 AC: 199 AN: 1342998 Hom.: 0 Cov.: 23 AF XY: 0.000168 AC XY: 113 AN XY: 673216

African (AFR) AF: 0.0000322 AC: 1 AN: 31096

American (AMR) AF: 0.000298 AC: 13 AN: 43678

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 38962

South Asian (SAS) AF: 0.00 AC: 0 AN: 81996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52892

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5552

European-Non Finnish (NFE) AF: 0.000175 AC: 176 AN: 1007426

Other (OTH) AF: 0.000107 AC: 6 AN: 56284

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152076 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74282

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

American (AMR) AF: 0.000262 AC: 4 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.000206 AC: 25

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	ALG8 congenital disorder of glycosylation (3)
-	1	-	ALG8 congenital disorder of glycosylation;C4693472:Polycystic liver disease 3 with or without kidney cysts (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.30
Sift	Benign	0.23	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.64
MPC		0.12
ClinPred		0.065	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.20
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs200068321; hg19: chr11-77815090;