chr22-33333777-C-T

Variant names:

• chr22-33333777-C-T
• rs5998876
• NM_133642.5:c.1287+3869G>A

Variant summary

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

The NM_133642.5(LARGE1):​c.1287+3869G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 151,982 control chromosomes in the GnomAD database, including 16,684 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 0.45 (16684 hom., cov: 32)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.734
• Publications: 2 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 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.1287+3869G>A		intron_variant	Intron 10 of 14	ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.1287+3869G>A		intron_variant	Intron 10 of 14	5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67600 AN: 151864 Hom.: 16658 Cov.: 32

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.433

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

GnomAD4 genome AF: 0.445 AC: 67669 AN: 151982 Hom.: 16684 Cov.: 32 AF XY: 0.443 AC XY: 32875 AN XY: 74292

African (AFR) AF: 0.675 AC: 27994 AN: 41460

American (AMR) AF: 0.395 AC: 6033 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1453 AN: 3472

East Asian (EAS) AF: 0.256 AC: 1320 AN: 5166

South Asian (SAS) AF: 0.470 AC: 2260 AN: 4812

European-Finnish (FIN) AF: 0.349 AC: 3676 AN: 10534

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.349 AC: 23728 AN: 67968

Other (OTH) AF: 0.428 AC: 903 AN: 2110

Alfa AF: 0.376 Hom.: 47521

Bravo AF: 0.458

Asia WGS AF: 0.335 AC: 1166 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.40
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs5998876; hg19: chr22-33729763;