rs28939378

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_019109.5(ALG1):c.773C>T(p.Ser258Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000604 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S258S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 7.02

Publications

22 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: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ALG1 links:

ENSG00000260882 (HGNC:):

ENSG00000260882 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 16-5078789-C-T is Pathogenic according to our data. Variant chr16-5078789-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4724.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.773C>T	p.Ser258Leu	missense	Exon 7 of 13	NP_061982.3
ALG1	NM_001438123.1		c.773C>T	p.Ser258Leu	missense	Exon 7 of 12	NP_001425052.1	A0A804HJL6
ALG1	NM_001330504.2		c.440C>T	p.Ser147Leu	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.773C>T	p.Ser258Leu	missense	Exon 7 of 13	ENSP00000262374.5	Q9BT22-1
ALG1	ENST00000588623.5	TSL:1	c.440C>T	p.Ser147Leu	missense	Exon 8 of 14	ENSP00000468118.1	Q9BT22-2
ALG1	ENST00000591822.5	TSL:1	n.*674C>T		non_coding_transcript_exon	Exon 7 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000304

AC:

AN:

250018

AF XY:

0.000332

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000540

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000633

AC:

924

AN:

1460556

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

473

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33444

American (AMR)

AF:

0.0000895

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4942

European-Non Finnish (NFE)

AF:

0.000798

AC:

887

AN:

1111766

Other (OTH)

AF:

0.000382

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

120

181

241

301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41454

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68028

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000101

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000771

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 (12)

not provided (3)

Congenital disorder of glycosylation (2)

Encephalopathy (1)

Finnish congenital nephrotic syndrome (1)

Inborn genetic diseases (1)

ALG12-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.68

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.8

PhyloP100

7.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.046

Polyphen

0.96

Vest4

0.62

MVP

0.95

MPC

0.18

ClinPred

0.44

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.72

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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