Variant chr16-5082676-A-G details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-5082676-A-G is Pathogenic according to our data. Variant chr16-5082676-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5082676-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5 link	c.1187+3A>G	splice_region_variant, intron_variant	Intron 11 of 12	ENST00000262374.10	NP_061982.3	Q9BT22-1
ALG1	NM_001330504.2 link	c.854+3A>G	splice_region_variant, intron_variant	Intron 11 of 12		NP_001317433.1	Q9BT22-2
ALG1	XM_017023457.3 link	c.1148+3A>G	splice_region_variant, intron_variant	Intron 10 of 11		XP_016878946.1	A0A804HJL6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10 link	c.1187+3A>G		splice_region_variant, intron_variant	Intron 11 of 12	1	NM_019109.5	ENSP00000262374.5		Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

18

AN:

152218

Hom.:

0

Cov.:

33

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

GnomAD3 exomes

AF:

0.000100

AC:

25

AN:

249520

Hom.:

0

AF XY:

0.000111

AC XY:

15

AN XY:

135146

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 SAS 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.:

0

Cov.:

34

AF XY:

0.000227

AC XY:

165

AN XY:

725798

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000291

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000118

AC:

18

AN:

152218

Hom.:

0

Cov.:

33

AF XY:

0.0000941

AC XY:

7

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

0

Bravo

AF:

0.000117

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG1-congenital disorder of glycosylation

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous c.1187+3A>G variant in ALG1 was identified by our study in one individual with congenital disorder of glycosylation. The c.1187+3A>G variant in ALG1 has been reported in 1 individual with congenital disorder of glycosylation (PMID: 26931382), and has been identified in 0.01906% (24/125942) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs369160589). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and the presence of this variant in combination with a reported pathogenic variant and in an individual with congenital disorder of glycosylation increases the likelihood that the c.1187+3A>G variant is pathogenic (PMID: 26931382; Variation ID: 4724). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing and cDNA analysis by the NIH Undiagnosed Diseases Network demonstrated this variant has a damaging effect (Variation ID: 224118). A biomarker for loss of function in ALG1, xeno-tetrasaccharide, was detected in the serum of an individual with this variant in the compound heterozygous state (PMID: 26931382). Loss of function of the ALG1 gene is an established disease mechanism in autosomal recessive congenital disorder of glycosylation and there is evidence that this gene is necessary for survival (PMID: 26931382). However, these types of assays may not accurately represent biological function and this information is not predictive enough to determine pathogenicity. This variant has also been reported as likely pathogenic in ClinVar by multiple submitters (Variation ID: 224118). Two additional variants in this splice region have been reported pathogenic in ClinVar, raising the possibility that this splice region is a mutational hot spot (Variation ID: 95934, 194107). In summary, this variant meets criteria to be classified as pathogenic for congenital disorder of glycosylation in an autosomal recessive manner based on the predicted impact of the variant and our findings in the literature and ClinVar. ACMG/AMP Criteria applied: PM2, PM3, PS3, PVS1, PM1_Supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2024	This sequence change falls in intron 11 of the ALG1 gene. It does not directly change the encoded amino acid sequence of the ALG1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs369160589, gnomAD 0.02%). This variant has been observed in individual(s) with congenital disorders of glycosylation (PMID: 26931382, 32190976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224118). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 22, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2024	Variant summary: ALG1 c.1187+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 prime splicing donor site. One predict the variant weakens a 5 prime donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Bowling_2017). The variant allele was found at a frequency of 0.0001 in 249520 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALG1 causing Congenital Disorder Of Glycosylation Type 1K (0.0001 vs 0.0011), allowing no conclusion about variant significance. c.1187+3A>G has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1K. These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28554332, 32190976, 34567092, 26931382, 38736633). ClinVar contains an entry for this variant (Variation ID: 224118). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Pathogenic and reported on 07-27-2021 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ik (MIM#608540). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. 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). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (25 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated glycosyl transferases group 1 domain (DECIPHER). (I) 0702 - Other premature termination variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as likely pathogenic/pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic multiple times in ClinVar, and as compound heterozygous with p.(Ser258Leu) in an affected individual with type I congenital disorder of glycosylation (PMIDs: 26931382, 28554332). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 23, 2017	Clinical genome sequencing revealed 3 variants of uncertain significance in the ALG1 gene. Multiple lines of computational evidence support a deleterious effect of these variants on the gene or gene product. cDNA experiments performed on a research basis demonstrated that the paternally inherited variant (c.1187+3A>G) is damaging. The maternally inherited variants are rare and are not present in the 1000 Genomes Project nor the Exome Aggregate Consortium (ExAC) databases. Based on these findings, the clinical team elevated these variants to likely pathogenic. -

Congenital disorder of glycosylation

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 27, 2020	VARIANT INTERPRETATION: The c.1187+3A>G variant in ALG1 has been reported in three individuals with congenital disorders of glycosylation. One is homozygous and two are compound heterozygous with the p.Ser258Leu variant in ALG1 (Ng 2016 26931382, Bowling 2017 28554332, SCV001164452.1). It has also been identified in 0.02% (23/112692) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 224118). This variant is located in the 5' splice region. In vitro qPCR analysis demonstrates a retention of exon 11 and a stop gain after the addition of 84 nucleotides, consistent with pathogenicity (Bowling 2017 28554332). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Congenital disorders of glycosylation. ACMG/AMP Criteria applied: PS3, PM3_Strong. -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	May 25, 2017	- -

ALG1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2022

The ALG1 c.1187+3A>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state in individuals with congenital disorder of glycosylation (Ng et al. 2016. PubMed ID: 26931382; Bowling et al. 2017. PubMed ID: 28554332; Burdick et al. 2020. PubMed ID: 32190976). 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). An additional genome study also confirmed that this variant disrupted splicing (Burdick et al. 2020. PubMed ID: 32190976). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-5132677-A-G). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2022

Non-canonical splice site variant demonstrated to result in loss of function (Bowling et al., 2017); This variant is associated with the following publications: (PMID: 26931382, 28554332, 32190976) -

Congenital disorder of glycosylation type I

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The heterozygous c.1187+3A>G variant in ALG1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 1483545), in one individual with intrauterine growth restriction,microcephaly, brain abnormalities, and hypertonia. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 1483545). The c.1187+3A>G variant in ALG1 has been reported in two individuals with congenital disorder of glycosylation type I (PMID: 26931382, SCV001164452.1), but has been identified in 0.02% (16/68040) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs369160589). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 224118) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. Of the two affected individuals previously reported, one was a homozygote (SCV001164452.1) and one was a compound heterozygote who carried a reported likely pathogenic variant in trans (PMID: 26931382, PMID: 28554332, ClinVar Variation ID: 4724), which increases the likelihood that the c.1187+3A>G variant is pathogenic. 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). This variant is located in the 5‚Äô splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive congenital disorder of glycosylation type I. ACMG/AMP Criteria applied: PS3_Moderate, PM3, PM2_Supporting, PP4 (Richards 2015). -

Encephalopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

23

DANN

Benign

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr16-5082676-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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