rs121908340

Positions:

• chr16-5075447-C-A
• chr16-5075447-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1 PM2 PP3 PP5_Moderate

The ENST00000262374.10(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 same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG1 ENST00000262374.10 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.38

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript ENST00000262374.10 (ALG1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 4726
• 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 id is 690326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-5075447-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG1	NM_019109.5	c.450C>A	p.Ser150Arg	missense_variant	4/13	ENST00000262374.10	NP_061982.3
ALG1	NM_001330504.2	c.117C>A	p.Ser39Arg	missense_variant	4/13		NP_001317433.1
ALG1	XM_017023457.3	c.450C>A	p.Ser150Arg	missense_variant	4/12		XP_016878946.1
ALG1	XR_007064892.1	n.457C>A		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.450C>A	p.Ser150Arg	missense_variant	4/13	1	NM_019109.5	ENSP00000262374	P1

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

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 25, 2017

- -

ALG1-congenital disorder of glycosylation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

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
MutationTaster	Benign	1.0	D;D;D
Sift4G	Benign	0.13	T
MVP		0.77
ClinPred		0.98	D
GERP RS		5.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908340; hg19: chr16-5125448;