rs387906926

Variant names:

• chr16-5075431-G-A
• rs387906926
• NM_019109.5:c.434G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_019109.5(ALG1):​c.434G>A​(p.Gly145Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 5.20

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-5075431-G-A is Pathogenic according to our data. Variant chr16-5075431-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30537.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5	c.434G>A	p.Gly145Asp	missense_variant	Exon 4 of 13	ENST00000262374.10	NP_061982.3
ALG1	NM_001330504.2	c.101G>A	p.Gly34Asp	missense_variant	Exon 4 of 13		NP_001317433.1
ALG1	XM_017023457.3	c.434G>A	p.Gly145Asp	missense_variant	Exon 4 of 12		XP_016878946.1
ALG1	XR_007064892.1	n.441G>A		non_coding_transcript_exon_variant	Exon 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.434G>A	p.Gly145Asp	missense_variant	Exon 4 of 13	1	NM_019109.5	ENSP00000262374.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ALG1-congenital disorder of glycosylation Pathogenic:2 Uncertain:1

Feb 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ALG1 function (PMID: 26931382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ALG1 protein function. ClinVar contains an entry for this variant (Variation ID: 30537). This missense change has been observed in individual(s) with congenital disorders of glycosylation (PMID: 20679665). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 145 of the ALG1 protein (p.Gly145Asp). -

Nov 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 15, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Gly145Asp variant in ALG1 was identified by our study in two siblings with Congenital Disorder of Glycosylation. This variant was identified in the literature in the compound heterozygous state alongside the pathogenic variant, p.Ser258Leu in a 10-month old affected female proband (Dupre et al. 2010; PMID: 20679665). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly145Asp variant is uncertain. -

not specified Uncertain:1

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALG1 c.434G>A (p.Gly145Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes. c.434G>A has been reported in the literature in compound heterozygous individuals affected with Congenital Disorder Of Glycosylation Type 1K (Dupre_2010, Ng_2016, Xue_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in relatively normal effect on supporting growth at permissive temperature but failure to support growth at restrictive temperatures in a yeast complementation assay (Ng_2016). The following publications have been ascertained in the context of this evaluation (PMID: 20679665, 26931382, 37204045). ClinVar contains an entry for this variant (Variation ID: 30537). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.59	D
Sift4G	Benign	0.17	T
MVP		0.88
ClinPred		0.75	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906926; hg19: chr16-5125432; COSMIC: COSV99276082; COSMIC: COSV99276082;