dbSNP rs185149177: ALG9:p.Pro513Leu (chr11-111836229-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_024740.2(ALG9):c.1538C>T(p.Pro513Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,614,054 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 17 hom. )

Consequence

ALG9
NM_024740.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.92

Publications

5 publications found

Variant links:

Genes affected

ALG9 (HGNC:15672): (ALG9 alpha-1,2-mannosyltransferase) This gene encodes an alpha-1,2-mannosyltransferase enzyme that functions in lipid-linked oligosaccharide assembly. Mutations in this gene result in congenital disorder of glycosylation type Il. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ALG9 Gene-Disease associations (from GenCC):

ALG9-associated autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
ALG9-congenital disorder of glycosylation
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
autosomal dominant polycystic kidney disease
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Gillessen-Kaesbach-Nishimura syndrome
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ALG9 links:

ENSG00000258529 (HGNC:):

ENSG00000258529 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_024740.2, 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008098453).

BP6

Variant 11-111836229-G-A is Benign according to our data. Variant chr11-111836229-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00203 (309/152286) while in subpopulation SAS AF = 0.00581 (28/4820). AF 95% confidence interval is 0.00413. There are 1 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024740.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG9	NM_024740.2	MANE Select	c.1538C>T	p.Pro513Leu	missense	Exon 13 of 15	NP_079016.2	Q9H6U8-3
ALG9	NM_001441203.1		c.1538C>T	p.Pro513Leu	missense	Exon 13 of 16	NP_001428132.1
ALG9	NM_001352417.1		c.1517C>T	p.Pro506Leu	missense	Exon 13 of 16	NP_001339346.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG9	ENST00000616540.5	TSL:1 MANE Select	c.1538C>T	p.Pro513Leu	missense	Exon 13 of 15	ENSP00000482437.1	Q9H6U8-3
ENSG00000258529	ENST00000622211.4	TSL:2	c.2216C>T	p.Pro739Leu	missense	Exon 17 of 19	ENSP00000482396.1	A0A087WZ62
ALG9	ENST00000614444.4	TSL:1	c.1517C>T	p.Pro506Leu	missense	Exon 13 of 15	ENSP00000484200.1	Q9H6U8-1

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00257

AC:

641

AN:

249506

AF XY:

0.00287

show subpopulations

Gnomad AFR exome

AF:

0.000581

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00351

AC:

5128

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

2642

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33472

American (AMR)

AF:

0.000827

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00299

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00677

AC:

584

AN:

86252

European-Finnish (FIN)

AF:

0.000505

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00374

AC:

4162

AN:

1111936

Other (OTH)

AF:

0.00328

AC:

198

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

319

638

956

1275

1594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

178

356

534

712

890

<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:

0.00203

AC:

309

AN:

152286

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41560

American (AMR)

AF:

0.00137

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00581

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00310

AC:

211

AN:

68036

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00265

Hom.:

Bravo

AF:

0.00190

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

ALG9 congenital disorder of glycosylation (1)

ALG9-related disorder (1)

Gillessen-Kaesbach-Nishimura syndrome;C2931006:ALG9 congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.034

MetaRNN

Benign

0.0081

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.0

PhyloP100

7.9

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.17

Sift

Benign

0.10

Sift4G

Benign

0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.55

Mutation Taster

=80/20

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

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