rs3922872

Variant names:

• chr22-49904240-T-C
• rs3922872
• NM_024105.4:c.1177A>G
• ALG12 p.Ile393Val

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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:6
• Conservation: PhyloP100: 5.02
• Publications: 29 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Ambry Genetics

ENSG00000273192 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.1177A>G	p.Ile393Val	missense	Exon 9 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.1177A>G	p.Ile393Val	missense	Exon 9 of 10	ENSP00000333813.5	Q9BV10
	ALG12	ENST00000905517.1		c.1177A>G	p.Ile393Val	missense	Exon 9 of 10	ENSP00000575576.1
	ALG12	ENST00000905518.1		c.1177A>G	p.Ile393Val	missense	Exon 9 of 10	ENSP00000575577.1

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

GnomAD2 exomes AF: 0.110 AC: 27722 AN: 251308 AF XY: 0.117

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 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

African (AFR) AF: 0.0420 AC: 1407 AN: 33480

American (AMR) AF: 0.0720 AC: 3221 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3829 AN: 26132

East Asian (EAS) AF: 0.0482 AC: 1914 AN: 39680

South Asian (SAS) AF: 0.199 AC: 17197 AN: 86258

European-Finnish (FIN) AF: 0.125 AC: 6683 AN: 53418

Middle Eastern (MID) AF: 0.0990 AC: 571 AN: 5768

European-Non Finnish (NFE) AF: 0.115 AC: 127753 AN: 1111994

Other (OTH) AF: 0.113 AC: 6812 AN: 60396

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

African (AFR) AF: 0.0455 AC: 1888 AN: 41538

American (AMR) AF: 0.0852 AC: 1303 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 507 AN: 3470

East Asian (EAS) AF: 0.0425 AC: 220 AN: 5176

South Asian (SAS) AF: 0.189 AC: 908 AN: 4812

European-Finnish (FIN) AF: 0.122 AC: 1292 AN: 10586

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7886 AN: 67972

Other (OTH) AF: 0.0825 AC: 174 AN: 2110

Alfa AF: 0.110 Hom.: 2044

Bravo AF: 0.0850

Asia WGS AF: 0.129 AC: 452 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.114

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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Varity_R		0.30
gMVP		0.66
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3922872;

hg19: chr22-50297888;

COSMIC: COSV58206577;