rs62233155

Variant names:

• chr22-49904470-C-T
• rs62233155
• NM_024105.4:c.1029G>A
• ALG12 p.Ala343Ala

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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Ambry Genetics

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024105.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG12	NM_024105.4	MANE Select	c.1029G>A	p.Ala343Ala	synonymous	Exon 8 of 10	NP_077010.1	Q9BV10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG12	ENST00000330817.11	TSL:1 MANE Select	c.1029G>A	p.Ala343Ala	synonymous	Exon 8 of 10	ENSP00000333813.5	Q9BV10
	ALG12	ENST00000905517.1		c.1029G>A	p.Ala343Ala	synonymous	Exon 8 of 10	ENSP00000575576.1
	ALG12	ENST00000905518.1		c.1029G>A	p.Ala343Ala	synonymous	Exon 8 of 10	ENSP00000575577.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	ALG12-congenital disorder of glycosylation (2)
-	-	2	not provided (2)
-	-	1	ALG12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs62233155;

hg19: chr22-50298118;

COSMIC: COSV58208634;