dbSNP rs45574638: ALG9:c.406-7C>T (chr11-111865258-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_024740.2(ALG9):c.406-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,548,022 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 78 hom., cov: 33)

Exomes 𝑓: 0.033 ( 828 hom. )

Consequence

ALG9
NM_024740.2 splice_region, intron

Scores

Splicing: ADA: 0.00006998

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.852

Publications

3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
autosomal dominant polycystic kidney disease
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
Gillessen-Kaesbach-Nishimura syndrome
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ALG9 links:

ENSG00000258529 (HGNC:):

ENSG00000258529 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 11-111865258-G-A is Benign according to our data. Variant chr11-111865258-G-A is described in ClinVar as Benign. ClinVar VariationId is 96134.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 = 0.0252 (3831/152152) while in subpopulation NFE AF = 0.0362 (2461/67974). AF 95% confidence interval is 0.035. There are 78 homozygotes in GnomAd4. There are 1894 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 78 AR,AD 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	Effect	Exon Rank	Protein	UniProt
ALG9	NM_024740.2	MANE Select	c.406-7C>T	splice_region intron	N/A	NP_079016.2	Q9H6U8-3
ALG9	NM_001441203.1		c.406-7C>T	splice_region intron	N/A	NP_001428132.1
ALG9	NM_001352417.1		c.406-7C>T	splice_region intron	N/A	NP_001339346.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALG9	ENST00000616540.5	TSL:1 MANE Select	c.406-7C>T	splice_region intron	N/A	ENSP00000482437.1	Q9H6U8-3
ENSG00000258529	ENST00000622211.4	TSL:2	c.1105-7C>T	splice_region intron	N/A	ENSP00000482396.1	A0A087WZ62
ALG9	ENST00000614444.4	TSL:1	c.406-7C>T	splice_region intron	N/A	ENSP00000484200.1	Q9H6U8-1

Frequencies

GnomAD3 genomes

AF:

0.0252

AC:

3830

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00602

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0336

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00828

Gnomad FIN

AF:

0.0399

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0362

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.0251

AC:

3942

AN:

157232

AF XY:

0.0253

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.0208

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.000185

Gnomad FIN exome

AF:

0.0351

Gnomad NFE exome

AF:

0.0367

Gnomad OTH exome

AF:

0.0263

GnomAD4 exome

AF:

0.0326

AC:

45528

AN:

1395870

Hom.:

828

Cov.:

AF XY:

0.0319

AC XY:

21974

AN XY:

688562

show subpopulations

African (AFR)

AF:

0.00520

AC:

163

AN:

31342

American (AMR)

AF:

0.0215

AC:

754

AN:

35140

Ashkenazi Jewish (ASJ)

AF:

0.0255

AC:

639

AN:

25080

East Asian (EAS)

AF:

0.0000841

AC:

AN:

35668

South Asian (SAS)

AF:

0.0111

AC:

870

AN:

78474

European-Finnish (FIN)

AF:

0.0323

AC:

1594

AN:

49384

Middle Eastern (MID)

AF:

0.0180

AC:

102

AN:

5674

European-Non Finnish (NFE)

AF:

0.0369

AC:

39715

AN:

1077160

Other (OTH)

AF:

0.0291

AC:

1688

AN:

57948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

1946

3892

5837

7783

9729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1514

3028

4542

6056

7570

<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:

0.0252

AC:

3831

AN:

152152

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1894

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00600

AC:

249

AN:

41510

American (AMR)

AF:

0.0335

AC:

513

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3468

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.00849

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0399

AC:

422

AN:

10582

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0362

AC:

2461

AN:

67974

Other (OTH)

AF:

0.0336

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

196

392

589

785

981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0323

Hom.:

Bravo

AF:

0.0242

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

ALG9 congenital disorder of glycosylation (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.1

(source)

DANN

Benign

0.78

PhyloP100

0.85

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.040

SpliceAI score (max)

0.030

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