1-63370979-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Moderate

The NM_013339.4(ALG6):ā€‹c.2T>Cā€‹(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000005 in 1,598,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

ALG6
NM_013339.4 start_lost

Scores

7
6
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.17
Variant links:
Genes affected
ALG6 (HGNC:23157): (ALG6 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic. [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.

PVS1
Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 7 codons. Genomic position: 63370996. Lost 0.012 part of the original CDS.
PS1
Another start lost variant in NM_013339.4 (ALG6) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 554144
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-63370979-T-C is Pathogenic according to our data. Variant chr1-63370979-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558047.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG6NM_013339.4 linkc.2T>C p.Met1? start_lost Exon 2 of 15 ENST00000263440.6 NP_037471.2 Q9Y672

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG6ENST00000263440.6 linkc.2T>C p.Met1? start_lost Exon 2 of 15 5 NM_013339.4 ENSP00000263440.5 Q9Y672

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000484
AC:
7
AN:
1446584
Hom.:
0
Cov.:
28
AF XY:
0.00000694
AC XY:
5
AN XY:
720712
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:
0.00000637
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ALG6-congenital disorder of glycosylation 1C Pathogenic:1
Apr 25, 2018
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T;T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.90
.;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
-0.031
T
PROVEAN
Benign
-2.2
N;N
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Vest4
0.94
MutPred
1.0
Gain of catalytic residue at M1 (P = 0.0216);Gain of catalytic residue at M1 (P = 0.0216);
MVP
0.89
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.80
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs1387214955; hg19: chr1-63836650; API