rs8135963

Positions:

• chr22-49907828-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024105.4(ALG12):​c.885A>G​(p.Ala295Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,613,820 control chromosomes in the GnomAD database, including 59,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (13919 hom., cov: 32)
  • Exomes 𝑓: 0.23 (45826 hom.)
• Consequence: ALG12 NM_024105.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.39

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 22-49907828-T-C is Benign according to our data. Variant chr22-49907828-T-C is described in ClinVar as [Benign]. Clinvar id is 96102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-49907828-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG12	NM_024105.4	c.885A>G	p.Ala295Ala	synonymous_variant	7/10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.885A>G	p.Ala295Ala	synonymous_variant	7/10		XP_016884425.1
ALG12	XM_017028937.2	c.885A>G	p.Ala295Ala	synonymous_variant	7/11		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.885A>G	p.Ala295Ala	synonymous_variant	7/10	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000486602.1	c.90A>G	p.Ala30Ala	synonymous_variant	1/4	3		ENSP00000420630.1
ALG12	ENST00000492791.1	n.414A>G		non_coding_transcript_exon_variant	3/6	3		ENSP00000417387.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54348 AN: 151950 Hom.: 13859 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.306

GnomAD3 exomes AF: 0.256 AC: 64213 AN: 251256 Hom.: 11252 AF XY: 0.258 AC XY: 35082 AN XY: 135848

Gnomad AFR exome AF: 0.742

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.426

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.229 AC: 334278 AN: 1461752 Hom.: 45826 Cov.: 37 AF XY: 0.234 AC XY: 170123 AN XY: 727166

Gnomad4 AFR exome AF: 0.753

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.425

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.358 AC: 54463 AN: 152068 Hom.: 13919 Cov.: 32 AF XY: 0.354 AC XY: 26284 AN XY: 74328

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.310

Alfa AF: 0.243 Hom.: 7458

Bravo AF: 0.370

Asia WGS AF: 0.331 AC: 1152 AN: 3476

EpiCase AF: 0.204

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

ALG12-congenital disorder of glycosylation Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8135963; hg19: chr22-50301476; COSMIC: COSV58207567; COSMIC: COSV58207567;