chr16-5081009-A-C

Variant names:

• chr16-5081009-A-C
• rs267606651
• NM_019109.5:c.1025A>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 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
• Publications: 3 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_019109.5
• 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 CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5081009-A-C is described in CliVar as Pathogenic/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 rank	MANE	Protein	UniProt
ALG1	NM_019109.5	c.1025A>C	p.Gln342Pro	missense_variant	Exon 10 of 13	ENST00000262374.10	NP_061982.3
ALG1	NM_001438123.1	c.986A>C	p.Gln329Pro	missense_variant	Exon 9 of 12		NP_001425052.1
ALG1	NM_001330504.2	c.692A>C	p.Gln231Pro	missense_variant	Exon 10 of 13		NP_001317433.1
ALG1	XR_007064892.1	n.*24A>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.1025A>C	p.Gln342Pro	missense_variant	Exon 10 of 13	1	NM_019109.5	ENSP00000262374.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000428 AC: 1 AN: 233530 AF XY: 0.00000779

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39056

South Asian (SAS) AF: 0.00 AC: 0 AN: 86056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 0.0000543 AC: 60 AN: 1104308

Other (OTH) AF: 0.0000169 AC: 1 AN: 59294

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

Jun 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs267606651, gnomAD 0.0009%). 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. -

Mar 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Dec 28, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
PhyloP100		3.5
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
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606651; hg19: chr16-5131010;