1-63419380-C-T

Variant names:

• chr1-63419380-C-T
• rs121908443
• NM_013339.4:c.998C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_013339.4(ALG6):​c.998C>T​(p.Ala333Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000609 in 1,608,452 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915431: Functional studies in yeast with a hypoglycosylation phenotype showed that the p.Ala333Val variant was able to only partially restore glycosylation, whereas glycosylation was fully restored with the wild type protein (Imbach et al. 1999" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A333G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: ALG6 NM_013339.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 6.45
• Publications: 37 publications found

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]

ITGB3BP (HGNC:6157): (integrin subunit beta 3 binding protein) This gene encodes a transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families, thyroid hormone receptors and retinoid X receptors. This protein also acts as a corepressor of NF-kappaB-dependent signaling. This protein induces apoptosis in breast cancer cells through a caspase 2-mediated signaling pathway. This protein is also a component of the centromere-specific histone H3 variant nucleosome associated complex (CENP-NAC) and may be involved in mitotic progression by recruiting the histone H3 variant CENP-A to the centromere. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915431: Functional studies in yeast with a hypoglycosylation phenotype showed that the p.Ala333Val variant was able to only partially restore glycosylation, whereas glycosylation was fully restored with the wild type protein (Imbach et al. 1999; Westphal et al. 2000).; SCV001213979: Experimental studies have shown that this missense change affects ALG6 function (PMID: 10359825, 10914684, 11106564).; SCV005395145: "At least one publication reports experimental evidence that this variant impacts protein function in yeast (Imbach_1999)."; SCV001767459: Published functional studies demonstrate that the A333V variant severely impairs ALG6 protein function and leads to incomplete CPY glycosylation (Imbach et al., 2000; Westphal et al., 2003)
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 1-63419380-C-T is Pathogenic according to our data. Variant chr1-63419380-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013339.4. 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
	ALG6	NM_013339.4	MANE Select	c.998C>T	p.Ala333Val	missense	Exon 12 of 15	NP_037471.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG6	ENST00000263440.6	TSL:5 MANE Select	c.998C>T	p.Ala333Val	missense	Exon 12 of 15	ENSP00000263440.5	Q9Y672
	ALG6	ENST00000948329.1		c.998C>T	p.Ala333Val	missense	Exon 12 of 15	ENSP00000618388.1
	ALG6	ENST00000920026.1		c.983C>T	p.Ala328Val	missense	Exon 12 of 15	ENSP00000590085.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151760 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000440 AC: 11 AN: 249886 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000638 AC: 93 AN: 1456692 Hom.: 0 Cov.: 29 AF XY: 0.0000704 AC XY: 51 AN XY: 724612

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.0000225 AC: 1 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85312

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000757 AC: 84 AN: 1109302

Other (OTH) AF: 0.0000498 AC: 3 AN: 60216

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151760 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74108

African (AFR) AF: 0.0000242 AC: 1 AN: 41330

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000231 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	ALG6-congenital disorder of glycosylation 1C (9)
4	-	-	not provided (4)
1	-	-	ALG6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		6.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Vest4		0.91
MVP		0.95
MPC		0.92
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.64
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.12		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: rs121908443; hg19: chr1-63885051;