22-49904017-T-C

Variant names:

• chr22-49904017-T-C
• rs878852984
• NM_024105.4:c.1288A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024105.4(ALG12):​c.1288A>G​(p.Thr430Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T430P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG12 NM_024105.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72
• Publications: 1 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: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000273192 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1288A>G	p.Thr430Ala	missense	Exon 10 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.1288A>G	p.Thr430Ala	missense	Exon 10 of 10	ENSP00000333813.5	Q9BV10
	ALG12	ENST00000905517.1		c.1288A>G	p.Thr430Ala	missense	Exon 10 of 10	ENSP00000575576.1
	ALG12	ENST00000905518.1		c.1288A>G	p.Thr430Ala	missense	Exon 10 of 10	ENSP00000575577.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.045	D
Polyphen		0.90	P
Vest4		0.35
MutPred		0.66		Loss of loop (P = 0.0986)
MVP		0.92
MPC		0.46
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.12
gMVP		0.81
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs878852984; hg19: chr22-50297665;