Genetic Variant ALG1:p.Cys5Arg (chr16-5071862-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019109.5(ALG1):c.13T>C(p.Cys5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000826 in 1,452,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C5G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.507

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11647189).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	NM_019109.5	MANE Select	c.13T>C	p.Cys5Arg	missense	Exon 1 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.13T>C	p.Cys5Arg	missense	Exon 1 of 12	NP_001425052.1	A0A804HJL6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG1	ENST00000262374.10	TSL:1 MANE Select	c.13T>C	p.Cys5Arg	missense	Exon 1 of 13	ENSP00000262374.5	Q9BT22-1
ALG1	ENST00000588623.5	TSL:1	c.-125-1089T>C		intron	N/A	ENSP00000468118.1	Q9BT22-2
ALG1	ENST00000591822.5	TSL:1	n.13T>C		non_coding_transcript_exon	Exon 1 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

231650

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000888

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:

0.00000826

AC:

AN:

1452310

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

722582

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33392

American (AMR)

AF:

0.0000902

AC:

AN:

44346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.00

AC:

AN:

85674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5386

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110572

Other (OTH)

AF:

0.00

AC:

AN:

60070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG1-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.4

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.079

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.24

M_CAP

Benign

0.047

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

PhyloP100

-0.51

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

REVEL

Benign

0.17

Sift

Benign

0.033

Sift4G

Benign

0.15

Polyphen

0.0

Vest4

0.35

MutPred

0.65

Gain of disorder (P = 0.0242)

MVP

0.36

MPC

0.064

ClinPred

0.030

GERP RS

-2.2

PromoterAI

0.093

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.17

gMVP

0.60

Mutation Taster

=95/5

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over