22-49909202-A-T

Variant names:

• chr22-49909202-A-T
• rs4075331
• NM_024105.4:c.768+42T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024105.4(ALG12):​c.768+42T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ALG12 NM_024105.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.16
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG12	NM_024105.4	c.768+42T>A		intron_variant	Intron 6 of 9	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.768+42T>A		intron_variant	Intron 6 of 9		XP_016884425.1
ALG12	XM_017028937.2	c.768+42T>A		intron_variant	Intron 6 of 10		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.768+42T>A		intron_variant	Intron 6 of 9	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000492791.1	n.297+42T>A		intron_variant	Intron 2 of 5	3		ENSP00000417387.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435548 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 715814

African (AFR) AF: 0.00 AC: 0 AN: 33032

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 85810

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088412

Other (OTH) AF: 0.00 AC: 0 AN: 59488

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.050
DANN	Benign	0.49
PhyloP100		-3.2

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: rs4075331; hg19: chr22-50302850;