rs76707654

Positions:

• chr22-49913667-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024105.4(ALG12):​c.99G>A​(p.Val33=) 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:3
• Conservation: PhyloP100: 0.378

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG12	NM_024105.4	c.99G>A	p.Val33=	synonymous_variant	2/10	ENST00000330817.11
ALG12	XM_017028936.2	c.99G>A	p.Val33=	synonymous_variant	2/10
ALG12	XM_017028937.2	c.99G>A	p.Val33=	synonymous_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG12	ENST00000330817.11	c.99G>A	p.Val33=	synonymous_variant	2/10	1	NM_024105.4	P1

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

GnomAD3 exomes AF: 0.0193 AC: 4855 AN: 251366 Hom.: 161 AF XY: 0.0180 AC XY: 2449 AN XY: 135904

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 SAS exome AF: 0.0286

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

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0293

Gnomad4 FIN exome AF: 0.00236

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0187

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0273

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0249 Hom.: 53

Bravo AF: 0.0464

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALG12-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.1
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs76707654; hg19: chr22-50307315;