dbSNP rs151173406: ALG1:p.Arg276Trp (chr16-5078842-C-T) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP3PP5_Very_Strong

The NM_019109.5(ALG1):c.826C>T(p.Arg276Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,786 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 (★★). ClinVar reports functional evidence for this variant: "SCV004122827: A functional study examining the impact of the variant using an alg1-deficient yeast strain found that the variant was not able to rescue the growth-deficient phenotype to the same extent as the wild type protein (Ng_2016), however, as this assay is not quantitative it does not necessarily allow strong conclusions about the variant effect." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.77

Publications

5 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, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ALG1 links:

ENSG00000260882 (HGNC:):

ENSG00000260882 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_019109.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004122827: A functional study examining the impact of the variant using an alg1-deficient yeast strain found that the variant was not able to rescue the growth-deficient phenotype to the same extent as the wild type protein (Ng_2016), however, as this assay is not quantitative it does not necessarily allow strong conclusions about the variant effect.; SCV001785527: The variant impaired the normal function of ALG1 (Ng et al., 2016); PMID: 26931382, 20679665, 27670784

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-5078842-C-T is Pathogenic according to our data. 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG1	NM_019109.5	MANE Select	c.826C>T	p.Arg276Trp	missense	Exon 7 of 13	NP_061982.3
ALG1	NM_001438123.1		c.826C>T	p.Arg276Trp	missense	Exon 7 of 12	NP_001425052.1	A0A804HJL6
ALG1	NM_001330504.2		c.493C>T	p.Arg165Trp	missense	Exon 7 of 13	NP_001317433.1	Q9BT22-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG1	ENST00000262374.10	TSL:1 MANE Select	c.826C>T	p.Arg276Trp	missense	Exon 7 of 13	ENSP00000262374.5	Q9BT22-1
ALG1	ENST00000588623.5	TSL:1	c.493C>T	p.Arg165Trp	missense	Exon 8 of 14	ENSP00000468118.1	Q9BT22-2
ALG1	ENST00000591822.5	TSL:1	n.*727C>T		non_coding_transcript_exon	Exon 7 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248830

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.0000640

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459606

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4398

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111742

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41452

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000760

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG1-congenital disorder of glycosylation (5)

Congenital disorder of glycosylation (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.6

PhyloP100

2.8

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.90

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.80

Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over