22-49903787-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_024105.4(ALG12):c.*51A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,578,790 control chromosomes in the GnomAD database, including 58,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 13931 hom., cov: 33)

Exomes 𝑓: 0.23 ( 44882 hom. )

Consequence

ALG12
NM_024105.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.243

Publications

41 publications found

Variant links:

Genes affected

ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]

ALG12 Gene-Disease associations (from GenCC):

ALG12-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ALG12 links:

ENSG00000273192 (HGNC:):

ENSG00000273192 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 (REVEL=0.027).

BP6

Variant 22-49903787-T-C is Benign according to our data. Variant chr22-49903787-T-C is described in ClinVar as [Benign]. Clinvar id is 342038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALG12	NM_024105.4 link	c.*51A>G	3_prime_UTR_variant	Exon 10 of 10	ENST00000330817.11	NP_077010.1	Q9BV10A0A024R4V6
ALG12	XM_017028936.2 link	c.1238+392A>G	intron_variant	Intron 9 of 9		XP_016884425.1
ALG12	XM_017028937.2 link	c.1238+392A>G	intron_variant	Intron 9 of 10		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALG12	ENST00000330817.11 link	c.*51A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_024105.4	ENSP00000333813.5	Q9BV10
ALG12	ENST00000486602.1 link	c.536A>G	p.His179Arg	missense_variant	Exon 4 of 4	3		ENSP00000420630.1	H7C5R7
ENSG00000273192	ENST00000610245.1 link	n.1560T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
ALG12	ENST00000492791.1 link	n.*337A>G		downstream_gene_variant		3		ENSP00000417387.1	H7C4I6

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

54366

AN:

152056

Hom.:

13872

Cov.:

show subpopulations

Gnomad AFR

AF:

0.729

Gnomad AMI

AF:

0.468

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.413

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.306

GnomAD2 exomes

AF:

0.254

AC:

63079

AN:

248116

AF XY:

0.259

show subpopulations

Gnomad AFR exome

AF:

0.744

Gnomad AMR exome

AF:

0.152

Gnomad ASJ exome

AF:

0.305

Gnomad EAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.165

Gnomad NFE exome

AF:

0.205

Gnomad OTH exome

AF:

0.232

GnomAD4 exome

AF:

0.229

AC:

326462

AN:

1426616

Hom.:

44882

Cov.:

AF XY:

0.234

AC XY:

166766

AN XY:

711634

show subpopulations

African (AFR)

AF:

0.753

AC:

24710

AN:

32824

American (AMR)

AF:

0.160

AC:

7149

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

7704

AN:

25914

East Asian (EAS)

AF:

0.137

AC:

5425

AN:

39464

South Asian (SAS)

AF:

0.426

AC:

36481

AN:

85542

European-Finnish (FIN)

AF:

0.169

AC:

8912

AN:

52836

Middle Eastern (MID)

AF:

0.327

AC:

1861

AN:

5688

European-Non Finnish (NFE)

AF:

0.203

AC:

219059

AN:

1080484

Other (OTH)

AF:

0.256

AC:

15161

AN:

59206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

13841

27682

41523

55364

69205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.358

AC:

54480

AN:

152174

Hom.:

13931

Cov.:

AF XY:

0.353

AC XY:

26275

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.729

AC:

30285

AN:

41518

American (AMR)

AF:

0.223

AC:

3408

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1055

AN:

3472

East Asian (EAS)

AF:

0.145

AC:

748

AN:

5160

South Asian (SAS)

AF:

0.412

AC:

1987

AN:

4826

European-Finnish (FIN)

AF:

0.166

AC:

1766

AN:

10612

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14069

AN:

67980

Other (OTH)

AF:

0.310

AC:

654

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1415

2830

4246

5661

7076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.266

Hom.:

14228

Bravo

AF:

0.370

Asia WGS

AF:

0.332

AC:

1157

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALG12-congenital disorder of glycosylation

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.1

(source)

DANN

Benign

0.21

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism (auto)

(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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22-49903787-T-C

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