rs61995925

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_024079.5(ALG8):​c.803G>T​(p.Arg268Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ALG8
NM_024079.5 missense

Scores

15
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

Publications

13 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG8NM_024079.5 linkc.803G>T p.Arg268Leu missense_variant Exon 8 of 13 ENST00000299626.10 NP_076984.2 Q9BVK2-1A0A024R5K5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG8ENST00000299626.10 linkc.803G>T p.Arg268Leu missense_variant Exon 8 of 13 1 NM_024079.5 ENSP00000299626.5 Q9BVK2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000797
AC:
2
AN:
250846
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461538
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727090
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39680
South Asian (SAS)
AF:
0.0000580
AC:
5
AN:
86216
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53374
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111808
Other (OTH)
AF:
0.00
AC:
0
AN:
60382
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;D;D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;.;D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H;H;H;.;.;.
PhyloP100
7.3
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-6.7
D;D;.;D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.;.;.
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.96
MutPred
0.95
Gain of ubiquitination at K273 (P = 0.0683);Gain of ubiquitination at K273 (P = 0.0683);Gain of ubiquitination at K273 (P = 0.0683);.;.;.;
MVP
0.99
MPC
0.72
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.80
gMVP
0.87
Mutation Taster
=7/93
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.28
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.28
Position offset: 25

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

Publications

Other links and lift over

dbSNP: rs61995925; hg19: chr11-77823791; API