rs387906273

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_005787.6(ALG3):c.165C>T(p.Gly55Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,359,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ALG3
NM_005787.6 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.777

Variant links:

Genes affected

ALG3 (HGNC:23056): (ALG3 alpha-1,3- mannosyltransferase) This gene encodes a member of the ALG3 family. The encoded protein catalyses the addition of the first dol-P-Man derived mannose in an alpha 1,3 linkage to Man5GlcNAc2-PP-Dol. Defects in this gene have been associated with congenital disorder of glycosylation type Id (CDG-Id) characterized by abnormal N-glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

ALG3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-184248776-G-A is Pathogenic according to our data. Variant chr3-184248776-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG3	NM_005787.6 link	c.165C>T	p.Gly55Gly	synonymous_variant	Exon 1 of 9	ENST00000397676.8	NP_005778.1	Q92685-1
ALG3	NM_001006941.2 link	c.52+450C>T		intron_variant	Intron 1 of 8		NP_001006942.1	Q92685-2
ALG3	NR_024533.1 link	n.196C>T		non_coding_transcript_exon_variant	Exon 1 of 8
ALG3	NR_024534.1 link	n.190+6C>T		splice_region_variant, intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG3	ENST00000397676.8 link	c.165C>T	p.Gly55Gly	synonymous_variant	Exon 1 of 9	1	NM_005787.6	ENSP00000380793.3		Q92685-1

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

144924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000425

AC:

AN:

235522

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000964

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1214886

Hom.:

Cov.:

AF XY:

0.0000567

AC XY:

AN XY:

599386

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

26174

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

36586

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

17132

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

18198

Gnomad4 SAS exome

AF:

0.0000120

AC:

AN:

83508

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

31850

Gnomad4 NFE exome

AF:

0.0000629

AC:

AN:

953352

Gnomad4 Remaining exome

AF:

0.0000456

AC:

AN:

43888

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.0000138

AC:

AN:

144924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70600

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000304

AC:

0.0000303951

AN:

0.0000303951

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000632

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG3-congenital disorder of glycosylation

Pathogenic:4

May 02, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The homozygous c.154+6C>T variant in ALG3 was identified by our study in two siblings with facial dysmorphism, muscle weakness, absent speech, and delayed gross motor development (PMID: 32389449). The c.154+6C>T variant in ALG3 has been previously reported in three individuals with congenital disorder of glycosylation type 1d (PMID: 15108280, PMID: 27172925, PMID: 28122681), but has been identified in 0.003% (2/65800) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs387906273). 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: 2128) with conflicting interpretations of pathogenicity. Of the 3 affected individuals previously reported, two were homozygotes (PMID: 28122681, PMID: 15108280) and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 27172925, ClinVar Variation ID: 1053045), which increases the likelihood that the c.154+6C>T variant is pathogenic. The phenotype of two individuals homozygous for this variant is highly specific for congenital disorder of glycosylation type 1d based on their abnormal lipid-linked oligosaccharide profiles including the presence of truncated Man5-GlcNAc2, consistent with disease (PMID: 28122681, PMID: 15108280). RT-PCR analysis of RNA from affected tissue showed altered splicing of exon 1, leading to a 35bp deletion (c.160_196del), frameshift, and premature truncation (PMID: 15108280). This variant is located in the 5' 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 1d. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PM3, PP4 (Richards 2015). -

Dec 10, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 55 of the ALG3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ALG3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ALG3-congenital disorder of glycosylation (PMID: 15108280, 27172925, 31067009). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2128). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Jun 05, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is demonstrated to cause aberrant splicing and result in loss of function (Denecke et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30487145, 31618474, 27172925, 31067009, 15108280, 32389449) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=40/60

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.85

Position offset: -31

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over