rs369160589

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPP3_ModeratePP5_Strong

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 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: 3 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000746579: cDNA experiments performed on a research basis demonstrated that the paternally inherited variant (c.1187+3A>G) is damaging.; SCV000827732: Studies have shown that this variant results in retention of intron 11 of the ALG1 gene, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 28554332).; SCV001164452: cDNA analysis by the NIH Undiagnosed Diseases Network demonstrated this variant has a damaging effect (Variation ID: 224118). PMID: 26931382; SCV003921901: Quantitative PCR from a patient's blood RNA showed the variant led to increased retention of intron 11, which is predicted to result in a premature stop codon and nonsense-mediated decay (NMD) of RNA (PMID: 28554332).; SCV000491480: Non-canonical splice site variant demonstrated to result in loss of function (Bowling et al., 2017); SCV001653091: "In vitro qPCR analysis demonstrates a retention of exon 11 and a stop gain after the addition of 84 nucleotides, consistent with pathogenicity." PMID:28554332; SCV003922320: RT-PCR analysis performed on affected tissue showed evidence of intron retention before exon 12, leading to a premature stop codon after addition of 84bp (PMID: 28554332).; SCV004108945: RT-PCR analysis indicated this variant leads to retention of intron 11, resulting in addition of 84 nucleotides (28 codons) and a stop gain (Bowling et al. 2017. PubMed ID: 28554332; González-Domínguez et al. 2021. PubMed ID: 34567092).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000264 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s). ClinVar submissions strongly and reliably favor pathogenicity (13/14 total P/LP).

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_regionintron	Intron 11 of 12	Prot: NP_061982.3
	ALG1 NM_001438123.1		c.1148+3A>G	splice_regionintron	Intron 10 of 11	Prot: NP_001425052.1 UniProt:
	ALG1 NM_001330504.2		c.854+3A>G	splice_regionintron	Intron 11 of 12	Prot: NP_001317433.1 UniProt:

ALG1 NM_019109.5

MANE Select

HGVSc / HGVSpc.1187+3A>G

Exon rankIntron 11 of 12

splice_regionintron

Prot: NP_061982.3

ALG1 NM_001438123.1

HGVSc / HGVSpc.1148+3A>G

Exon rankIntron 10 of 11

splice_regionintron

Prot: NP_001425052.1UniProt: A0A804HJL6

ALG1 NM_001330504.2

HGVSc / HGVSpc.854+3A>G

Exon rankIntron 11 of 12

splice_regionintron

Prot: NP_001317433.1UniProt: Q9BT22-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ALG1 ENST00000262374.10	TSL:1MANE Select	c.1187+3A>G	splice_regionintron	Intron 11 of 12	Prot: ENSP00000262374.5 UniProt:
	ALG1 ENST00000588623.5	TSL:1	c.854+3A>G	splice_regionintron	Intron 12 of 13	Prot: ENSP00000468118.1 UniProt:
	ALG1 ENST00000591822.5	TSL:1	n.*1088+3A>G	splice_regionintron	Intron 11 of 12	Prot: ENSP00000467865.1 UniProt:

ALG1 ENST00000262374.10

TSL:1MANE Select

HGVSc / HGVSpc.1187+3A>G

Exon rankIntron 11 of 12

splice_regionintron

Prot: ENSP00000262374.5UniProt: Q9BT22-1

ALG1 ENST00000588623.5

TSL:1

HGVSc / HGVSpc.854+3A>G

Exon rankIntron 12 of 13

splice_regionintron

Prot: ENSP00000468118.1UniProt: Q9BT22-2

ALG1 ENST00000591822.5

TSL:1

HGVSc / HGVSpn.*1088+3A>G

Exon rankIntron 11 of 12

splice_regionintron

Prot: ENSP00000467865.1UniProt: 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	AF: 0.000118	AC:18	Hom:0	AN:152218	Cov:33
GnomAD2 exomes	AF: 0.000100	AC:25	Hom:	AN:249520	Cov:
GnomAD4 exome	AF: 0.000229	AC:334	Hom:0	AN:1458914	Cov:34
GnomAD4 genome	AF: 0.000118	AC:18	Hom:0	AN:152218	Cov:33
TOPMed (Bravo)	AF: 0.000117	AC:31	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000730	AC:4	Hom:0	AN:54788	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000247	AC:3	Hom:	AN:12132	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

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 pred.	Score	Prediction
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	6/94	disease causing (ClinVar)
PhyloP100	Benign	3.4

Showing 8 of 8 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs369160589;

hg19: chr16-5132677;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar