NM_024105.4:c.*363G>A

Variant names:

• chr22-49903475-C-T
• rs568473076
• NM_024105.4:c.*363G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_024105.4(ALG12):​c.*363G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 483,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: ALG12 NM_024105.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.126
• Publications: 0 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: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000273192 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.049).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (200/152308) while in subpopulation NFE AF = 0.0021 (143/68020). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*363G>A		3_prime_UTR	Exon 10 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.*363G>A		3_prime_UTR	Exon 10 of 10	ENSP00000333813.5	Q9BV10
	ALG12	ENST00000905517.1		c.*363G>A		3_prime_UTR	Exon 10 of 10	ENSP00000575576.1
	ALG12	ENST00000905518.1		c.*363G>A		3_prime_UTR	Exon 10 of 10	ENSP00000575577.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00107 AC: 148 AN: 138506 AF XY: 0.00108

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.000956

GnomAD4 exome AF: 0.00125 AC: 414 AN: 331546 Hom.: 0 Cov.: 0 AF XY: 0.00115 AC XY: 214 AN XY: 186810

African (AFR) AF: 0.000202 AC: 2 AN: 9894

American (AMR) AF: 0.000143 AC: 4 AN: 27978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11976

East Asian (EAS) AF: 0.00 AC: 0 AN: 11178

South Asian (SAS) AF: 0.00 AC: 0 AN: 59972

European-Finnish (FIN) AF: 0.00365 AC: 52 AN: 14236

Middle Eastern (MID) AF: 0.000343 AC: 1 AN: 2912

European-Non Finnish (NFE) AF: 0.00189 AC: 335 AN: 177350

Other (OTH) AF: 0.00125 AC: 20 AN: 16050

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00124 AC XY: 92 AN XY: 74464

African (AFR) AF: 0.000361 AC: 15 AN: 41570

American (AMR) AF: 0.00124 AC: 19 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ALG12-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.40
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs568473076; hg19: chr22-50297123;