rs76707654

Variant names:

• chr22-49913667-C-T
• rs76707654
• NM_024105.4:c.99G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024105.4(ALG12):​c.99G>A​(p.Val33Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,614,138 control chromosomes in the GnomAD database, including 738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (302 hom., cov: 33)
  • Exomes 𝑓: 0.014 (436 hom.)
• Consequence: ALG12 NM_024105.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.378
• Publications: 5 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)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 22-49913667-C-T is Benign according to our data. Variant chr22-49913667-C-T is described in ClinVar as Benign. ClinVar VariationId is 342060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.378 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

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.99G>A	p.Val33Val	synonymous	Exon 2 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.99G>A	p.Val33Val	synonymous	Exon 2 of 10	ENSP00000333813.5	Q9BV10
	ALG12	ENST00000905517.1		c.99G>A	p.Val33Val	synonymous	Exon 2 of 10	ENSP00000575576.1
	ALG12	ENST00000905518.1		c.99G>A	p.Val33Val	synonymous	Exon 2 of 10	ENSP00000575577.1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6307 AN: 152200 Hom.: 302 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0193 AC: 4855 AN: 251366 AF XY: 0.0180

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0142 AC: 20710 AN: 1461820 Hom.: 436 Cov.: 33 AF XY: 0.0144 AC XY: 10437 AN XY: 727208

African (AFR) AF: 0.125 AC: 4200 AN: 33480

American (AMR) AF: 0.0115 AC: 513 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 306 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0293 AC: 2526 AN: 86258

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53356

Middle Eastern (MID) AF: 0.0298 AC: 172 AN: 5768

European-Non Finnish (NFE) AF: 0.0106 AC: 11733 AN: 1112008

Other (OTH) AF: 0.0187 AC: 1130 AN: 60392

GnomAD4 genome AF: 0.0415 AC: 6324 AN: 152318 Hom.: 302 Cov.: 33 AF XY: 0.0407 AC XY: 3031 AN XY: 74484

African (AFR) AF: 0.119 AC: 4931 AN: 41554

American (AMR) AF: 0.0180 AC: 275 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4834

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 816 AN: 68034

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0260 Hom.: 56

Bravo AF: 0.0464

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0132

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.1
DANN	Benign	0.77
PhyloP100		0.38
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs76707654; hg19: chr22-50307315;