NM_024105.4:c.1029G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_024105.4(ALG12):​c.1029G>A​(p.Ala343Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,614,076 control chromosomes in the GnomAD database, including 1,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 93 hom., cov: 32)
Exomes 𝑓: 0.035 ( 1093 hom. )

Consequence

ALG12
NM_024105.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.307

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (REVEL=0.005).
BP6
Variant 22-49904470-C-T is Benign according to our data. Variant chr22-49904470-C-T is described in ClinVar as Benign. ClinVar VariationId is 342045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.307 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0269 (4087/152212) while in subpopulation NFE AF = 0.0383 (2604/67998). AF 95% confidence interval is 0.0371. There are 93 homozygotes in GnomAd4. There are 2024 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 93 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG12NM_024105.4 linkc.1029G>A p.Ala343Ala synonymous_variant Exon 8 of 10 ENST00000330817.11 NP_077010.1 Q9BV10A0A024R4V6
ALG12XM_017028936.2 linkc.1029G>A p.Ala343Ala synonymous_variant Exon 8 of 10 XP_016884425.1
ALG12XM_017028937.2 linkc.1029G>A p.Ala343Ala synonymous_variant Exon 8 of 11 XP_016884426.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG12ENST00000330817.11 linkc.1029G>A p.Ala343Ala synonymous_variant Exon 8 of 10 1 NM_024105.4 ENSP00000333813.5 Q9BV10
ALG12ENST00000486602.1 linkc.234G>A p.Ala78Ala synonymous_variant Exon 2 of 4 3 ENSP00000420630.1 H7C5R7
ENSG00000273192ENST00000610245.1 linkn.2243C>T non_coding_transcript_exon_variant Exon 1 of 1 6
ALG12ENST00000492791.1 linkn.522-86G>A intron_variant Intron 3 of 5 3 ENSP00000417387.1 H7C4I6

Frequencies

GnomAD3 genomes
AF:
0.0269
AC:
4088
AN:
152094
Hom.:
93
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00630
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.0181
Gnomad ASJ
AF:
0.0193
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00415
Gnomad FIN
AF:
0.0764
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0383
Gnomad OTH
AF:
0.0206
GnomAD2 exomes
AF:
0.0301
AC:
7564
AN:
251330
AF XY:
0.0300
show subpopulations
Gnomad AFR exome
AF:
0.00548
Gnomad AMR exome
AF:
0.00983
Gnomad ASJ exome
AF:
0.0237
Gnomad EAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.0782
Gnomad NFE exome
AF:
0.0428
Gnomad OTH exome
AF:
0.0300
GnomAD4 exome
AF:
0.0345
AC:
50490
AN:
1461864
Hom.:
1093
Cov.:
32
AF XY:
0.0338
AC XY:
24574
AN XY:
727230
show subpopulations
African (AFR)
AF:
0.00472
AC:
158
AN:
33480
American (AMR)
AF:
0.0101
AC:
453
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0231
AC:
603
AN:
26136
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39690
South Asian (SAS)
AF:
0.00561
AC:
484
AN:
86254
European-Finnish (FIN)
AF:
0.0791
AC:
4224
AN:
53416
Middle Eastern (MID)
AF:
0.00208
AC:
12
AN:
5768
European-Non Finnish (NFE)
AF:
0.0385
AC:
42806
AN:
1112000
Other (OTH)
AF:
0.0289
AC:
1747
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
3055
6110
9166
12221
15276
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
1502
3004
4506
6008
7510
<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:
0.0269
AC:
4087
AN:
152212
Hom.:
93
Cov.:
32
AF XY:
0.0272
AC XY:
2024
AN XY:
74420
show subpopulations
African (AFR)
AF:
0.00628
AC:
261
AN:
41530
American (AMR)
AF:
0.0180
AC:
276
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.0193
AC:
67
AN:
3466
East Asian (EAS)
AF:
0.000386
AC:
2
AN:
5176
South Asian (SAS)
AF:
0.00415
AC:
20
AN:
4820
European-Finnish (FIN)
AF:
0.0764
AC:
810
AN:
10598
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.0383
AC:
2604
AN:
67998
Other (OTH)
AF:
0.0203
AC:
43
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
212
424
637
849
1061
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
52
104
156
208
260
<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:
0.0361
Hom.:
191
Bravo
AF:
0.0214
Asia WGS
AF:
0.00491
AC:
17
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:5
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

- -

May 04, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ALG12-congenital disorder of glycosylation Benign:2
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. -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ALG12-related disorder Benign:1
Feb 24, 2020
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
CADD
Benign
7.0
DANN
Benign
0.43
PhyloP100
-0.31
Mutation Taster
=94/6
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs62233155; hg19: chr22-50298118; COSMIC: COSV58208634; API