rs369160589

Variant names:

• chr16-5082676-A-G
• rs369160589
• NM_019109.5:c.1187+3A>G

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O6_Supporting

The NM_019109.5(ALG1):c.1187+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The gene ALG1 is a known oncogene (CancerMine: 1 oncogene citations). The variant allele was found at a cumulative frequency of 0.000218 (AC=352) in the gnomAD database across 1,611,132 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000264. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV000746579: cDNA experiments performed on a research basis demonstrated that the paternally inherited variant (c.1187+3A>G) is damaging." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: ALG1 NM_019109.5 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:1 O:1
• Conservation: PhyloP100: 3.37
• Publications: 2 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Orphanet, ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Our verdict: Uncertain_significance. The variant received 1 points.

• O6: Computational evidence supports a deleterious/oncogenic effect; Splice-region variant — splicing algorithms predict an impact on splicing; supports O6

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_019109.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	NM_019109.5	MANE Select	c.1187+3A>G		splice_region intron	N/A	NP_061982.3
	ALG1	NM_001438123.1		c.1148+3A>G		splice_region intron	N/A	NP_001425052.1	A0A804HJL6
	ALG1	NM_001330504.2		c.854+3A>G		splice_region intron	N/A	NP_001317433.1	Q9BT22-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.1187+3A>G		splice_region intron	N/A	ENSP00000262374.5	Q9BT22-1
	ALG1	ENST00000588623.5	TSL:1	c.854+3A>G		splice_region intron	N/A	ENSP00000468118.1	Q9BT22-2
	ALG1	ENST00000591822.5	TSL:1	n.*1088+3A>G		splice_region intron	N/A	ENSP00000467865.1	K7EQK1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	0.000118	18	0	152218	33
GnomAD2 exomes	0.000100	25		249520
GnomAD4 exome	0.000229	334	0	1458914	34
GnomAD4 genome	0.000118	18	0	152218	33
TOPMed (Bravo)	0.000117	31	0	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.0000730	4	0	54788
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	0.000247	3		12132
UK10K	0.000264	2		7562

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000141	4	28420	0.000173	5	28844
SCHEMA(Schizophrenia)	0.0000519	6	115618	0.0000663	12	180992

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
8	-	-	ALG1-congenital disorder of glycosylation (9)
2	-	-	Congenital disorder of glycosylation (2)
1	-	-	ALG1-related disorder (1)
1	-	-	Congenital disorder of glycosylation type I (1)
1	-	-	Encephalopathy (1)
-	1	-	Fetal anomalies with a likely genetic cause (1)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	25
BayesDel_noAF	Benign	-	-0.32
CADD	Benign	-	23
DANN	Benign	-	0.96
GPN-Star LLR	N/A	-	-5.6
GPN-Star score	N/A	-	5.6
Mutation Taster	N/A	disease causing (ClinVar)	6/94
PhyloP100	Benign	-	3.4

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
dbscSNV1_ADA	Pathogenic	-	1.0
dbscSNV1_RF	Pathogenic	-	0.96
DS_DL_spliceai	Pathogenic	- Position offset: -3	0.66
Pangolin (max)	Pathogenic	-	0.55
Pangolin loss	Pathogenic	- Position offset: -3	0.55
SpliceAI score (max)	Pathogenic	- Details are displayed if max score is > 0.2	0.66

Showing 6 of 6 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs369160589;

hg19: chr16-5132677;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar