NM_024105.4:c.1029G>A

Variant names:

• chr22-49904470-C-T
• rs62233155
• NM_024105.4:c.1029G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.307
• Publications: 3 publications found

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

ENSG00000273192 (HGNC:):

ACMG classification

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
ALG12	NM_024105.4	c.1029G>A	p.Ala343Ala	synonymous_variant	Exon 8 of 10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.1029G>A	p.Ala343Ala	synonymous_variant	Exon 8 of 10		XP_016884425.1
ALG12	XM_017028937.2	c.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
ALG12	ENST00000330817.11	c.1029G>A	p.Ala343Ala	synonymous_variant	Exon 8 of 10	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000486602.1	c.234G>A	p.Ala78Ala	synonymous_variant	Exon 2 of 4	3		ENSP00000420630.1
ENSG00000273192	ENST00000610245.1	n.2243C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
ALG12	ENST00000492791.1	n.522-86G>A		intron_variant	Intron 3 of 5	3		ENSP00000417387.1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4088 AN: 152094 Hom.: 93 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.0269 AC: 4087 AN: 152212 Hom.: 93 Cov.: 32 AF XY: 0.0272 AC XY: 2024 AN XY: 74420

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

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

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

Other links and lift over

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