rs768733117

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_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

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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ALG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ALG1	NM_019109.5 link	c.863-2A>G	splice_acceptor_variant, intron_variant	Intron 7 of 12	ENST00000262374.10	NP_061982.3
ALG1	NM_001438123.1 link	c.862+184A>G	intron_variant	Intron 7 of 11		NP_001425052.1
ALG1	NM_001330504.2 link	c.530-2A>G	splice_acceptor_variant, intron_variant	Intron 7 of 12		NP_001317433.1
ALG1	XR_007064892.1 link	n.870-2A>G	splice_acceptor_variant, intron_variant	Intron 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10 link	c.863-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 12	1	NM_019109.5	ENSP00000262374.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

230076

AF XY:

0.0000157

show subpopulations

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:

AN:

1448340

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

720908

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000101

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42432

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111650

Other (OTH)

AF:

0.00

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG1-congenital disorder of glycosylation

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 7 of the ALG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALG1 are known to be pathogenic (PMID: 20679665, 23806237). This variant is present in population databases (rs768733117, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 580876). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0

.;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

.;.;.

MetaRNN

Benign

0.0

.;.;.

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

7.8

PROVEAN

Benign

0.0

.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.

Sift4G

Pathogenic

0.0

.;.;.

Vest4

0.0

GERP RS

3.6

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over