rs3922872

Variant names:

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

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: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

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 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 rank	MANE	Protein	UniProt
ALG12	NM_024105.4	c.1177A>G	p.Ile393Val	missense_variant	Exon 9 of 10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.1177A>G	p.Ile393Val	missense_variant	Exon 9 of 10		XP_016884425.1
ALG12	XM_017028937.2	c.1177A>G	p.Ile393Val	missense_variant	Exon 9 of 11		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.1177A>G	p.Ile393Val	missense_variant	Exon 9 of 10	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000486602.1	c.382A>G	p.Ile128Val	missense_variant	Exon 3 of 4	3		ENSP00000420630.1
ALG12	ENST00000492791.1	n.584A>G		non_coding_transcript_exon_variant	Exon 5 of 6	3		ENSP00000417387.1
ENSG00000273192	ENST00000610245.1	n.2013T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

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

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Oct 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALG12-congenital disorder of glycosylation Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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
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
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

Other links and lift over

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