Genetic Variant NM_019109.5:c.191C>A (chr16-5072040-C-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_019109.5(ALG1):c.191C>A(p.Thr64Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00387 in 1,587,760 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T64I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 16 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.87

Publications

10 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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_019109.5

BP4

Computational evidence support a benign effect (MetaRNN=0.009994924).

BP6

Variant 16-5072040-C-A is Benign according to our data. Variant chr16-5072040-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 193421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00241 (365/151218) while in subpopulation NFE AF = 0.00395 (268/67812). AF 95% confidence interval is 0.00356. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

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.191C>A	p.Thr64Asn	missense	Exon 1 of 13	NP_061982.3
ALG1	NM_001438123.1		c.191C>A	p.Thr64Asn	missense	Exon 1 of 12	NP_001425052.1	A0A804HJL6
ALG1	NM_001330504.2		c.-389C>A		upstream_gene	N/A	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.191C>A	p.Thr64Asn	missense	Exon 1 of 13	ENSP00000262374.5	Q9BT22-1
ALG1	ENST00000588623.5	TSL:1	c.-125-911C>A		intron	N/A	ENSP00000468118.1	Q9BT22-2
ALG1	ENST00000591822.5	TSL:1	n.191C>A		non_coding_transcript_exon	Exon 1 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes

AF:

0.00242

AC:

366

AN:

151100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000901

Gnomad AMI

AF:

0.00442

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000854

Gnomad FIN

AF:

0.000381

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00395

Gnomad OTH

AF:

0.00385

GnomAD2 exomes

AF:

0.00234

AC:

463

AN:

198180

AF XY:

0.00259

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.000762

Gnomad ASJ exome

AF:

0.00691

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000457

Gnomad NFE exome

AF:

0.00383

Gnomad OTH exome

AF:

0.00308

GnomAD4 exome

AF:

0.00402

AC:

5776

AN:

1436542

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

2867

AN XY:

712352

show subpopulations

African (AFR)

AF:

0.000546

AC:

AN:

32990

American (AMR)

AF:

0.000843

AC:

AN:

41508

Ashkenazi Jewish (ASJ)

AF:

0.00829

AC:

213

AN:

25680

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38484

South Asian (SAS)

AF:

0.00122

AC:

101

AN:

82962

European-Finnish (FIN)

AF:

0.000552

AC:

AN:

50732

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00467

AC:

5128

AN:

1099072

Other (OTH)

AF:

0.00409

AC:

243

AN:

59376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

366

731

1097

1462

1828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.00241

AC:

365

AN:

151218

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

145

AN XY:

73852

show subpopulations

African (AFR)

AF:

0.000899

AC:

AN:

41170

American (AMR)

AF:

0.00118

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5062

South Asian (SAS)

AF:

0.000855

AC:

AN:

4680

European-Finnish (FIN)

AF:

0.000381

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00395

AC:

268

AN:

67812

Other (OTH)

AF:

0.00381

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00349

Hom.:

Bravo

AF:

0.00243

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.00287

AC:

ExAC

AF:

0.00189

AC:

226

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

ALG1-congenital disorder of glycosylation (1)

ALG1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.8

PhyloP100

3.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.33

Sift

Benign

0.079

Sift4G

Benign

0.28

Polyphen

0.95

Vest4

0.61

MVP

0.86

MPC

0.13

ClinPred

0.035

GERP RS

4.0

PromoterAI

-0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.16

gMVP

0.71

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over