chr1-63402348-G-A

Variant names:

• chr1-63402348-G-A
• rs199682486
• NM_013339.4:c.257+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_013339.4(ALG6):​c.257+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,591,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000568303: Functional studies indicate that c.257+5G>A (reported using alternate nomenclature IVS3+5G>A) transfected cells produce a nonfunctional enzyme that is unable to restore normal glycosylation in a yeast strain lacking functional ALG6 (Westphal et al., 2000);; SCV000538013: This variant is shown to cause the skipping of exon 3, and produces a nonfunctional enzyme as shown by its inability to restore normal glycosylation in a yeast strain lacking a functional ALG6 (Westphal et al. 2000).; SCV000824414: Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID:10924277).; SCV001194124: Functional assessments of this variant are available in the literature (PMID:10924277, 10914684).; SCV003844924: One publication reports experimental evidence evaluating the effect of transforming ALG6 missing exon 3 in an alg6-deficient strain of S. cerevisiae, finding that it is unable restore glycosylation activity (Westphal_2000).; SCV004889719: Functional studies demonstrate that this alteration causes skipping of coding exon 3 leading to a nonfunctional protein (Imbach, 2000; Westphal, 2000).; SCV005344651: Functional studies have demonstrated this variant leads to exon skipping (Westphal et al. 2000. PubMed ID: 10924277).".

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: ALG6 NM_013339.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 9.55
• Publications: 8 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000568303: Functional studies indicate that c.257+5G>A (reported using alternate nomenclature IVS3+5G>A) transfected cells produce a nonfunctional enzyme that is unable to restore normal glycosylation in a yeast strain lacking functional ALG6 (Westphal et al., 2000);; SCV000538013: This variant is shown to cause the skipping of exon 3, and produces a nonfunctional enzyme as shown by its inability to restore normal glycosylation in a yeast strain lacking a functional ALG6 (Westphal et al. 2000).; SCV000824414: Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 10924277).; SCV001194124: Functional assessments of this variant are available in the literature (PMID: 10924277, 10914684).; SCV003844924: One publication reports experimental evidence evaluating the effect of transforming ALG6 missing exon 3 in an alg6-deficient strain of S. cerevisiae, finding that it is unable restore glycosylation activity (Westphal_2000).; SCV004889719: Functional studies demonstrate that this alteration causes skipping of coding exon 3 leading to a nonfunctional protein (Imbach, 2000; Westphal, 2000).; SCV005344651: Functional studies have demonstrated this variant leads to exon skipping (Westphal et al. 2000. PubMed ID: 10924277).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-63402348-G-A is Pathogenic according to our data. Variant chr1-63402348-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 95529.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.257+5G>A		splice_region intron	N/A	NP_037471.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG6	ENST00000263440.6	TSL:5 MANE Select	c.257+5G>A		splice_region intron	N/A	ENSP00000263440.5	Q9Y672
	ALG6	ENST00000948329.1		c.257+5G>A		splice_region intron	N/A	ENSP00000618388.1
	ALG6	ENST00000920026.1		c.257+5G>A		splice_region intron	N/A	ENSP00000590085.1

Frequencies

GnomAD3 genomes AF: 0.000615 AC: 93 AN: 151150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000243

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: 0.00122

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000475 AC: 119 AN: 250774 AF XY: 0.000516

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000936

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000884 AC: 1273 AN: 1439864 Hom.: 0 Cov.: 28 AF XY: 0.000862 AC XY: 618 AN XY: 717262

African (AFR) AF: 0.0000909 AC: 3 AN: 33006

American (AMR) AF: 0.0000225 AC: 1 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25758

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 85830

European-Finnish (FIN) AF: 0.0000574 AC: 3 AN: 52308

Middle Eastern (MID) AF: 0.000532 AC: 3 AN: 5640

European-Non Finnish (NFE) AF: 0.00113 AC: 1234 AN: 1094444

Other (OTH) AF: 0.000471 AC: 28 AN: 59444

GnomAD4 genome AF: 0.000615 AC: 93 AN: 151150 Hom.: 0 Cov.: 31 AF XY: 0.000570 AC XY: 42 AN XY: 73744

African (AFR) AF: 0.000243 AC: 10 AN: 41218

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10314

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

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000922 Hom.: 0

Bravo AF: 0.000669

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	ALG6-congenital disorder of glycosylation 1C (14)
6	-	-	not provided (6)
1	-	-	ALG6-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.97
PhyloP100		9.6
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: -5

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

Other links and lift over

dbSNP: rs199682486; hg19: chr1-63868019;