chr16-5077459-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019109.5(ALG1):c.554T>G(p.Phe185Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,614,118 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 40 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 41 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.81

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, 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008822262).

BP6

Variant 16-5077459-T-G is Benign according to our data. Variant chr16-5077459-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 384255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1912/152258) while in subpopulation AFR AF = 0.0432 (1797/41550). AF 95% confidence interval is 0.0416. There are 40 homozygotes in GnomAd4. There are 915 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5 link	c.554T>G	p.Phe185Cys	missense_variant	Exon 5 of 13	ENST00000262374.10	NP_061982.3	Q9BT22-1
ALG1	NM_001438123.1 link	c.554T>G	p.Phe185Cys	missense_variant	Exon 5 of 12		NP_001425052.1
ALG1	NM_001330504.2 link	c.221T>G	p.Phe74Cys	missense_variant	Exon 5 of 13		NP_001317433.1	Q9BT22-2
ALG1	XR_007064892.1 link	n.561T>G		non_coding_transcript_exon_variant	Exon 5 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10 link	c.554T>G	p.Phe185Cys	missense_variant	Exon 5 of 13	1	NM_019109.5	ENSP00000262374.5		Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1902

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00337

AC:

848

AN:

251484

AF XY:

0.00258

show subpopulations

Gnomad AFR exome

AF:

0.0437

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00145

AC:

2123

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

934

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0463

AC:

1549

AN:

33478

American (AMR)

AF:

0.00286

AC:

128

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000174

AC:

194

AN:

1111990

Other (OTH)

AF:

0.00369

AC:

223

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

114

228

343

457

571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0126

AC:

1912

AN:

152258

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

915

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0432

AC:

1797

AN:

41550

American (AMR)

AF:

0.00445

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68020

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00483

Hom.:

Bravo

AF:

0.0146

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0407

AC:

179

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00429

AC:

521

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 31, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ALG1-congenital disorder of glycosylation

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 25, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.42

.;T;T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.82

.;T;T;T

MetaRNN

Benign

0.0088

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.6

.;L;.;.

PhyloP100

1.8

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-6.2

.;D;.;D

REVEL

Benign

0.24

Sift

Benign

0.11

.;T;.;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.074

.;B;.;.

Vest4

0.48

MVP

0.85

MPC

0.057

ClinPred

0.030

GERP RS

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.81

Mutation Taster

=92/8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over