dbSNP rs369160589: ALG1:c.1187+3A>G (chr16-5082676-A-G) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is 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 0.000259. 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:14U:1O:1

Conservation

PhyloP100: 3.37

Publications

2 publications found

Variant links:

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

ALG1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_019109.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 points.

PS3

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).

PM2

Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000259 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.

PP3

Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.

PP5

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

Gene	Transcript	Tags	HGVSc	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

Gene	Transcript	Tags	HGVSc	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

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000100

AC:

AN:

249520

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000229

AC:

334

AN:

1458914

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

725798

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33406

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000291

AC:

323

AN:

1111796

Other (OTH)

AF:

0.000166

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000583

Hom.:

Bravo

AF:

0.000117

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG1-congenital disorder of glycosylation (9)

Congenital disorder of glycosylation (2)

ALG1-related disorder (1)

Congenital disorder of glycosylation type I (1)

Encephalopathy (1)

Fetal anomalies with a likely genetic cause (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

3.4

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.66

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.66

Position offset: -3

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over