chr22-33273861-C-A

Variant names:

• chr22-33273861-C-A
• rs878945156
• NM_133642.5:c.*566G>T

Variant summary

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

The NM_133642.5(LARGE1):​c.*566G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 230,388 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: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 0 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: 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=-0.8).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133642.5. 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
	LARGE1	NM_133642.5	MANE Select	c.*566G>T		3_prime_UTR	Exon 15 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.*566G>T		3_prime_UTR	Exon 16 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.*566G>T		3_prime_UTR	Exon 15 of 15	NP_001349880.1	O95461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.*566G>T		3_prime_UTR	Exon 15 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.*566G>T		3_prime_UTR	Exon 16 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.*566G>T		3_prime_UTR	Exon 14 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000434 AC: 1 AN: 230388 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 117014

African (AFR) AF: 0.00 AC: 0 AN: 6730

American (AMR) AF: 0.00 AC: 0 AN: 7768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8644

East Asian (EAS) AF: 0.00 AC: 0 AN: 21080

South Asian (SAS) AF: 0.00 AC: 0 AN: 2372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1204

European-Non Finnish (NFE) AF: 0.00000673 AC: 1 AN: 148664

Other (OTH) AF: 0.00 AC: 0 AN: 15248

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.3
DANN	Benign	0.48
PhyloP100		0.32

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: rs878945156; hg19: chr22-33669847;