rs768733117

Variant names:

• chr16-5079062-A-G
• rs768733117
• NM_019109.5:c.863-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_019109.5(ALG1):​c.863-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,448,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ALG1 NM_019109.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.81
• Publications: 1 publications found

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 Gene-Disease associations (from GenCC):

• ALG1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027956989 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.6, offset of 30, new splice context is: cttctccatcctgctggcAGctt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-5079062-A-G is Pathogenic according to our data. Variant chr16-5079062-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 580876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019109.5. 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
	ALG1	NM_019109.5	MANE Select	c.863-2A>G		splice_acceptor intron	N/A	NP_061982.3
	ALG1	NM_001438123.1		c.862+184A>G		intron	N/A	NP_001425052.1
	ALG1	NM_001330504.2		c.530-2A>G		splice_acceptor intron	N/A	NP_001317433.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.863-2A>G		splice_acceptor intron	N/A	ENSP00000262374.5
	ALG1	ENST00000588623.5	TSL:1	c.530-2A>G		splice_acceptor intron	N/A	ENSP00000468118.1
	ALG1	ENST00000591822.5	TSL:1	n.*764-2A>G		splice_acceptor intron	N/A	ENSP00000467865.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000130 AC: 3 AN: 230076 AF XY: 0.0000157

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1448340 Hom.: 0 Cov.: 35 AF XY: 0.00000416 AC XY: 3 AN XY: 720908

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42432

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111650

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000170 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	ALG1-congenital disorder of glycosylation (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
GERP RS		3.6
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		Position offset: 2

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

Other links and lift over

dbSNP: rs768733117; hg19: chr16-5129063;