chr22-49903787-T-C

Position:

• chr22-49903787-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024105.4(ALG12):​c.*51A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,578,790 control chromosomes in the GnomAD database, including 58,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (13931 hom., cov: 33)
  • Exomes 𝑓: 0.23 (44882 hom.)
• Consequence: ALG12 NM_024105.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.243

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 22-49903787-T-C is Benign according to our data. Variant chr22-49903787-T-C is described in ClinVar as [Benign]. Clinvar id is 342038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-49903787-T-C is described in Lovd as [Benign].
• 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.*51A>G		3_prime_UTR_variant	10/10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.1238+392A>G		intron_variant			XP_016884425.1
ALG12	XM_017028937.2	c.1238+392A>G		intron_variant			XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.*51A>G		3_prime_UTR_variant	10/10	1	NM_024105.4	ENSP00000333813	P1
	ENST00000610245.1	n.1560T>C		non_coding_transcript_exon_variant	1/1
ALG12	ENST00000486602.1	c.539A>G	p.His180Arg	missense_variant	4/4	3		ENSP00000420630

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54366 AN: 152056 Hom.: 13872 Cov.: 33

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.306

GnomAD3 exomes AF: 0.254 AC: 63079 AN: 248116 Hom.: 10947 AF XY: 0.259 AC XY: 34851 AN XY: 134810

Gnomad AFR exome AF: 0.744

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.229 AC: 326462 AN: 1426616 Hom.: 44882 Cov.: 27 AF XY: 0.234 AC XY: 166766 AN XY: 711634

Gnomad4 AFR exome AF: 0.753

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.426

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.358 AC: 54480 AN: 152174 Hom.: 13931 Cov.: 33 AF XY: 0.353 AC XY: 26275 AN XY: 74400

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.310

Alfa AF: 0.225 Hom.: 6153

Bravo AF: 0.370

Asia WGS AF: 0.332 AC: 1157 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ALG12-congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1321; hg19: chr22-50297435; COSMIC: COSV58206677; COSMIC: COSV58206677;