16-5075447-C-A

Variant names:

• chr16-5075447-C-A
• rs121908340
• NM_019109.5:c.450C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM2 PP3 PP5_Moderate

The NM_019109.5(ALG1):​c.450C>A​(p.Ser150Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.38
• Publications: 6 publications found

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]

ALG1 Gene-Disease associations (from GenCC):

• ALG1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_019109.5 (ALG1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant 16-5075447-C-A is Pathogenic according to our data. Variant chr16-5075447-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 690326.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5	c.450C>A	p.Ser150Arg	missense_variant	Exon 4 of 13	ENST00000262374.10	NP_061982.3
ALG1	NM_001438123.1	c.450C>A	p.Ser150Arg	missense_variant	Exon 4 of 12		NP_001425052.1
ALG1	NM_001330504.2	c.117C>A	p.Ser39Arg	missense_variant	Exon 4 of 13		NP_001317433.1
ALG1	XR_007064892.1	n.457C>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.450C>A	p.Ser150Arg	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: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital disorder of glycosylation Pathogenic:1

May 25, 2017

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

ALG1-congenital disorder of glycosylation Pathogenic:1

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: 690326). This missense change has been observed in individual(s) with ALG1-congenital disorder of glycosylation (PMID: 14709599, 20679665, 26931382). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 150 of the ALG1 protein (p.Ser150Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.83	D
PhyloP100		7.4
Sift4G	Benign	0.13	T
MVP		0.77
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.60
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121908340; hg19: chr16-5125448;