chr22-33273429-T-C

Variant names:

• chr22-33273429-T-C
• rs886057455
• NM_133642.5:c.*998A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_133642.5(LARGE1):​c.*998A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 398,578 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -2.21
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*998A>G		3_prime_UTR	Exon 15 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.*998A>G		3_prime_UTR	Exon 16 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.*998A>G		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.*998A>G		3_prime_UTR	Exon 15 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.*998A>G		3_prime_UTR	Exon 16 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.*998A>G		3_prime_UTR	Exon 14 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000422 AC: 104 AN: 246358 Hom.: 1 Cov.: 0 AF XY: 0.000449 AC XY: 56 AN XY: 124828

African (AFR) AF: 0.00 AC: 0 AN: 7180

American (AMR) AF: 0.000135 AC: 1 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.00639 AC: 59 AN: 9240

East Asian (EAS) AF: 0.00 AC: 0 AN: 22894

South Asian (SAS) AF: 0.00 AC: 0 AN: 3032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20878

Middle Eastern (MID) AF: 0.000773 AC: 1 AN: 1294

European-Non Finnish (NFE) AF: 0.000171 AC: 27 AN: 158036

Other (OTH) AF: 0.000977 AC: 16 AN: 16370

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74378

African (AFR) AF: 0.000121 AC: 5 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000261

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	1	-	Muscular dystrophy-dystroglycanopathy type B6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.045
DANN	Benign	0.48
PhyloP100		-2.2

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: rs886057455; hg19: chr22-33669415;