Variant rs387906273 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000397676.8(ALG3):c.165C>T(p.Gly55=) 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. In-silico tool predicts a benign outcome for this variant. 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
ENST00000397676.8 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:

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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 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/exons	MANE	Protein
ALG3	NM_005787.6 linkuse as main transcript	c.165C>T	p.Gly55=	synonymous_variant	1/9	ENST00000397676.8	NP_005778.1
ALG3	NM_001006941.2 linkuse as main transcript	c.52+450C>T		intron_variant			NP_001006942.1
ALG3	NR_024533.1 linkuse as main transcript	n.196C>T		non_coding_transcript_exon_variant	1/8
ALG3	NR_024534.1 linkuse as main transcript	n.190+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG3	ENST00000397676.8 linkuse as main transcript	c.165C>T	p.Gly55=	synonymous_variant	1/9	1	NM_005787.6	ENSP00000380793	P1	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

GnomAD3 exomes

AF:

0.00000425

AC:

AN:

235522

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129924

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 SAS 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

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000629

Gnomad4 OTH exome

AF:

0.0000456

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

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:

0.0000304

Gnomad4 OTH

AF:

0.00

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

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 15108280, 31067009). ClinVar contains an entry for this variant (Variation ID: 2128). 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. This variant is not present in population databases (gnomAD no frequency). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 10, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2023

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

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