16-5078843-G-A

Variant names:

• chr16-5078843-G-A
• rs201975029
• NM_019109.5:c.827G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM5 BP4_Strong

The NM_019109.5(ALG1):​c.827G>A​(p.Arg276Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000772 in 1,611,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:2
• Conservation: PhyloP100: 7.03
• 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

ENSG00000260882 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-5078842-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06585652).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019109.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	NM_019109.5	MANE Select	c.827G>A	p.Arg276Gln	missense	Exon 7 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.827G>A	p.Arg276Gln	missense	Exon 7 of 12	NP_001425052.1
	ALG1	NM_001330504.2		c.494G>A	p.Arg165Gln	missense	Exon 7 of 13	NP_001317433.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.827G>A	p.Arg276Gln	missense	Exon 7 of 13	ENSP00000262374.5
	ALG1	ENST00000588623.5	TSL:1	c.494G>A	p.Arg165Gln	missense	Exon 8 of 14	ENSP00000468118.1
	ALG1	ENST00000591822.5	TSL:1	n.*728G>A		non_coding_transcript_exon	Exon 7 of 13	ENSP00000467865.1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000651 AC: 162 AN: 248660 AF XY: 0.000659

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000805 AC: 1175 AN: 1459596 Hom.: 0 Cov.: 41 AF XY: 0.000821 AC XY: 596 AN XY: 726148

African (AFR) AF: 0.0000898 AC: 3 AN: 33414

American (AMR) AF: 0.0000447 AC: 2 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000917 AC: 79 AN: 86150

European-Finnish (FIN) AF: 0.00216 AC: 115 AN: 53206

Middle Eastern (MID) AF: 0.000228 AC: 1 AN: 4388

European-Non Finnish (NFE) AF: 0.000841 AC: 935 AN: 1111734

Other (OTH) AF: 0.000648 AC: 39 AN: 60212

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74480

African (AFR) AF: 0.0000962 AC: 4 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000520 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 29, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Oct 30, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26931382, 20679665)

ALG1-related disorder Benign:1

Jun 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.066	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.94
MPC		0.27
ClinPred		0.28	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.86
Mutation Taster		=51/49	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201975029; hg19: chr16-5128844; COSMIC: COSV52157862; COSMIC: COSV52157862;