rs3922872

chr22-49904240-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.1177A>G(p.Ile393Val) variant causes a missense change. The variant allele was found at a frequency of 0.114 in 1,614,008 control chromosomes in the GnomAD database, including 11,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (772 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10501 hom.)
• Consequence: ALG12 NM_024105.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.02

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 (MetaRNN=0.0070717633).
• BP6: Variant 22-49904240-T-C is Benign according to our data. Variant chr22-49904240-T-C is described in ClinVar as [Benign]. Clinvar id is 96095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG12	NM_024105.4	c.1177A>G	p.Ile393Val	missense_variant	9/10	ENST00000330817.11
ALG12	XM_017028936.2	c.1177A>G	p.Ile393Val	missense_variant	9/10
ALG12	XM_017028937.2	c.1177A>G	p.Ile393Val	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG12	ENST00000330817.11	c.1177A>G	p.Ile393Val	missense_variant	9/10	1	NM_024105.4	P1
	ENST00000610245.1	n.2013T>C		non_coding_transcript_exon_variant	1/1
ALG12	ENST00000486602.1	c.385A>G	p.Ile129Val	missense_variant	3/4	3
ALG12	ENST00000492791.1	c.587A>G	p.His196Arg	missense_variant, NMD_transcript_variant	5/6	3

Frequencies

GnomAD3 genomes AF: 0.0943 AC: 14336 AN: 152042 Hom.: 763 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0851

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0790

GnomAD3 exomes AF: 0.110 AC: 27722 AN: 251308 Hom.: 1786 AF XY: 0.117 AC XY: 15903 AN XY: 135870

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.0694

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0341

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.116 AC: 169387 AN: 1461848 Hom.: 10501 Cov.: 33 AF XY: 0.119 AC XY: 86392 AN XY: 727220

Gnomad4 AFR exome AF: 0.0420

Gnomad4 AMR exome AF: 0.0720

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0482

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.0944 AC: 14362 AN: 152160 Hom.: 772 Cov.: 32 AF XY: 0.0949 AC XY: 7060 AN XY: 74378

Gnomad4 AFR AF: 0.0455

Gnomad4 AMR AF: 0.0852

Gnomad4 ASJ AF: 0.146

Gnomad4 EAS AF: 0.0425

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0825

Alfa AF: 0.109 Hom.: 1532

Bravo AF: 0.0850

TwinsUK AF: 0.115 AC: 428

ALSPAC AF: 0.111 AC: 428

ESP6500AA AF: 0.0456 AC: 201

ESP6500EA AF: 0.115 AC: 987

ExAC AF: 0.112 AC: 13597

Asia WGS AF: 0.129 AC: 452 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.114

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

ALG12-congenital disorder of glycosylation Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	5.8e-7	P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.069
MPC		0.51
ClinPred		0.072	T
GERP RS		4.3
Varity_R		0.30
gMVP		0.66

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: rs3922872; hg19: chr22-50297888; COSMIC: COSV58206577;