NM_019109.5:c.840G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_019109.5(ALG1):c.840G>C(p.Leu280Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 1,611,694 control chromosomes in the GnomAD database, including 2,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L280L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.047 ( 218 hom., cov: 33)

Exomes 𝑓: 0.050 ( 2079 hom. )

Consequence

ALG1
NM_019109.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.802

Publications

6 publications found

Variant links:

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

ALG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 16-5078856-G-C is Benign according to our data. Variant chr16-5078856-G-C is described in ClinVar as [Benign]. Clinvar id is 95937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.802 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5 link	c.840G>C	p.Leu280Leu	synonymous_variant	Exon 7 of 13	ENST00000262374.10	NP_061982.3	Q9BT22-1
ALG1	NM_001438123.1 link	c.840G>C	p.Leu280Leu	synonymous_variant	Exon 7 of 12		NP_001425052.1
ALG1	NM_001330504.2 link	c.507G>C	p.Leu169Leu	synonymous_variant	Exon 7 of 13		NP_001317433.1	Q9BT22-2
ALG1	XR_007064892.1 link	n.847G>C		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10 link	c.840G>C	p.Leu280Leu	synonymous_variant	Exon 7 of 13	1	NM_019109.5	ENSP00000262374.5		Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.0470

AC:

7155

AN:

152190

Hom.:

218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0517

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.0738

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0188

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0541

Gnomad OTH

AF:

0.0559

GnomAD2 exomes

AF:

0.0388

AC:

9626

AN:

248140

AF XY:

0.0385

show subpopulations

Gnomad AFR exome

AF:

0.0513

Gnomad AMR exome

AF:

0.0352

Gnomad ASJ exome

AF:

0.0676

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0205

Gnomad NFE exome

AF:

0.0529

Gnomad OTH exome

AF:

0.0509

GnomAD4 exome

AF:

0.0502

AC:

73191

AN:

1459386

Hom.:

2079

Cov.:

AF XY:

0.0487

AC XY:

35370

AN XY:

726032

show subpopulations

African (AFR)

AF:

0.0509

AC:

1702

AN:

33406

American (AMR)

AF:

0.0358

AC:

1598

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0683

AC:

1782

AN:

26098

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0100

AC:

863

AN:

86144

European-Finnish (FIN)

AF:

0.0205

AC:

1090

AN:

53174

Middle Eastern (MID)

AF:

0.0887

AC:

378

AN:

4260

European-Non Finnish (NFE)

AF:

0.0562

AC:

62498

AN:

1111714

Other (OTH)

AF:

0.0544

AC:

3277

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

4645

9290

13936

18581

23226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2314

4628

6942

9256

11570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0470

AC:

7162

AN:

152308

Hom.:

218

Cov.:

AF XY:

0.0441

AC XY:

3284

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0518

AC:

2155

AN:

41578

American (AMR)

AF:

0.0441

AC:

674

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0738

AC:

256

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.0112

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0188

AC:

200

AN:

10620

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0541

AC:

3681

AN:

68026

Other (OTH)

AF:

0.0553

AC:

117

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

347

695

1042

1390

1737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0432

Hom.:

Bravo

AF:

0.0490

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0594

EpiControl

AF:

0.0602

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 24, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALG1-congenital disorder of glycosylation

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALG1-related disorder

Benign:1

Dec 01, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.3

(source)

DANN

Benign

0.75

PhyloP100

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over