rs1555930118

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_024105.4(ALG12):​c.367G>A​(p.Gly123Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ALG12
NM_024105.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.80
Variant links:
Genes affected
ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a transmembrane_region Helical (size 20) in uniprot entity ALG12_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_024105.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG12NM_024105.4 linkc.367G>A p.Gly123Arg missense_variant Exon 4 of 10 ENST00000330817.11 NP_077010.1 Q9BV10A0A024R4V6
ALG12XM_017028936.2 linkc.367G>A p.Gly123Arg missense_variant Exon 4 of 10 XP_016884425.1
ALG12XM_017028937.2 linkc.367G>A p.Gly123Arg missense_variant Exon 4 of 11 XP_016884426.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG12ENST00000330817.11 linkc.367G>A p.Gly123Arg missense_variant Exon 4 of 10 1 NM_024105.4 ENSP00000333813.5 Q9BV10

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461780
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ALG12-congenital disorder of glycosylation Pathogenic:1
-
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Uncertain:1
May 03, 2020
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
2.9
M
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-7.5
D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.81
Gain of MoRF binding (P = 0.0055);
MVP
0.98
MPC
0.72
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.81
gMVP
0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555930118; hg19: chr22-50304184; API