22-33170601-C-T

Variant names:

• chr22-33170601-C-T
• rs4821132
• ENST00000610186.6:c.1878-3769G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000421232.1(LARGE1):​n.151-3769G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,916 control chromosomes in the GnomAD database, including 13,918 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 0.42 (13918 hom., cov: 31)
• Consequence: LARGE1 ENST00000421232.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 5 publications found

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]

LARGE1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy type B6

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000421232.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000610186.6	TSL:5	c.1878-3769G>A		intron	N/A	ENSP00000476364.2	V9GY39
	LARGE1	ENST00000608642.6	TSL:5	c.1731-3769G>A		intron	N/A	ENSP00000476866.2	V9GYK8
	LARGE1	ENST00000609799.6	TSL:5	c.1452-3769G>A		intron	N/A	ENSP00000476415.2	V9GY56

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64197 AN: 151798 Hom.: 13905 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.426

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

GnomAD4 genome AF: 0.423 AC: 64250 AN: 151916 Hom.: 13918 Cov.: 31 AF XY: 0.417 AC XY: 30959 AN XY: 74250

African (AFR) AF: 0.434 AC: 17974 AN: 41412

American (AMR) AF: 0.393 AC: 5996 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1446 AN: 3462

East Asian (EAS) AF: 0.153 AC: 792 AN: 5160

South Asian (SAS) AF: 0.311 AC: 1496 AN: 4808

European-Finnish (FIN) AF: 0.422 AC: 4449 AN: 10552

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.449 AC: 30473 AN: 67936

Other (OTH) AF: 0.422 AC: 891 AN: 2112

Alfa AF: 0.438 Hom.: 23770

Bravo AF: 0.429

Asia WGS AF: 0.245 AC: 852 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.8
DANN	Benign	0.46
PhyloP100		0.12

Splicing

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

Other links and lift over

dbSNP: rs4821132; hg19: chr22-33566587;