rs267606651

Positions:

• chr16-5081009-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_019109.5(ALG1):​c.1025A>C​(p.Gln342Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000426 in 1,433,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.46

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 16-5081009-A-C is Pathogenic according to our data. Variant chr16-5081009-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG1	NM_019109.5	c.1025A>C	p.Gln342Pro	missense_variant	10/13	ENST00000262374.10	NP_061982.3
ALG1	NM_001330504.2	c.692A>C	p.Gln231Pro	missense_variant	10/13		NP_001317433.1
ALG1	XM_017023457.3	c.986A>C	p.Gln329Pro	missense_variant	9/12		XP_016878946.1
ALG1	XR_007064892.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.1025A>C	p.Gln342Pro	missense_variant	10/13	1	NM_019109.5	ENSP00000262374	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233530 Hom.: 0 AF XY: 0.00000779 AC XY: 1 AN XY: 128324

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: 0.00000921

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000426 AC: 61 AN: 1433072 Hom.: 0 Cov.: 33 AF XY: 0.0000379 AC XY: 27 AN XY: 713104

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000543

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000866 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALG1-congenital disorder of glycosylation Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2023	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. Experimental studies have shown that this missense change affects ALG1 function (PMID: 14973782). 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: 4725). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1K (PMID: 14973782). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs267606651, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 342 of the ALG1 protein (p.Gln342Pro). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.1025A>C (p.Q342P) alteration is located in exon 10 (coding exon 10) of the ALG1 gene. This alteration results from an A to C substitution at nucleotide position 1025, causing the glutamine (Q) at amino acid position 342 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/233530) total alleles studied. The highest observed frequency was 0.001% (1/108578) of European (non-Finnish) alleles. This variant has been reported in trans with another ALG1 variant in an individual diagnosed with ALG1-related congenital disorder of glycosylation (Kranz, 2004). This amino acid position is not well conserved in available vertebrate species. Functional studies indicate this variant significantly impairs beta-mannosyltransferase activity and is unable to complement ALG1-deficient yeast cells (Li, 2017; Kranz, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Uncertain	0.77	.;D;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.2	.;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.10	.;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.020	.;B;.
Vest4		0.77
MutPred		0.83		.;Loss of sheet (P = 0.0817);.;
MVP		0.80
MPC		0.054
ClinPred		0.36	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267606651; hg19: chr16-5131010;