rs4821129

Variant names:

• chr22-33099542-G-A
• rs4821129
• XR_007067993.1:n.2702-32425C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XR_007067993.1(LARGE1):​n.2702-32425C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,116 control chromosomes in the GnomAD database, including 2,133 homozygotes. 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: 𝑓 0.15 (2133 hom., cov: 32)
• Consequence: LARGE1 XR_007067993.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792

Genes affected

LARGE1 (HGNC:6511): (LARGE xylosyl- and glucuronyltransferase 1) This gene encodes a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. The protein encoded by this gene is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in this gene cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	XR_007067993.1	n.2702-32425C>T		intron_variant	Intron 15 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22655 AN: 151998 Hom.: 2133 Cov.: 32

Gnomad AFR AF: 0.0661

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.187

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22654 AN: 152116 Hom.: 2133 Cov.: 32 AF XY: 0.149 AC XY: 11104 AN XY: 74362

Gnomad4 AFR AF: 0.0660

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.191

Alfa AF: 0.159 Hom.: 328

Bravo AF: 0.149

Asia WGS AF: 0.293 AC: 1017 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4821129; hg19: chr22-33495528;