rs387906273
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005787.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG3 | NM_005787.6 | c.165C>T | p.Gly55Gly | synonymous_variant | Exon 1 of 9 | ENST00000397676.8 | NP_005778.1 | |
ALG3 | NM_001006941.2 | c.52+450C>T | intron_variant | Intron 1 of 8 | NP_001006942.1 | |||
ALG3 | NR_024533.1 | n.196C>T | non_coding_transcript_exon_variant | Exon 1 of 8 | ||||
ALG3 | NR_024534.1 | n.190+6C>T | splice_region_variant, intron_variant | Intron 1 of 8 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000138 AC: 2AN: 144924Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000425 AC: 1AN: 235522Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 129924
GnomAD4 exome AF: 0.0000519 AC: 63AN: 1214886Hom.: 0 Cov.: 36 AF XY: 0.0000567 AC XY: 34AN XY: 599386
GnomAD4 genome AF: 0.0000138 AC: 2AN: 144924Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 70600
ClinVar
Submissions by phenotype
ALG3-congenital disorder of glycosylation Pathogenic:4
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. -
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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). -
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not provided Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at