chr22-33165760-T-C

Variant names:

• chr22-33165760-T-C
• rs743793
• ENST00000610186.6:c.*1003A>G

Variant summary

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

The ENST00000610186.6(LARGE1):​c.*1003A>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 0.426 in 151,992 control chromosomes in the GnomAD database, including 14,147 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 0.43 (14147 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: LARGE1 ENST00000610186.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• 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 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

ENSG00000232073 (HGNC:58379):

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 = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	XM_024452302.2	c.*1003A>G		3_prime_UTR_variant	Exon 15 of 15		XP_024308070.1
LARGE1	XM_047441606.1	c.*1003A>G		3_prime_UTR_variant	Exon 10 of 10		XP_047297562.1
LARGE1	XR_002958722.2	n.2638+876A>G		intron_variant	Intron 14 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000610186.6	c.*1003A>G		3_prime_UTR_variant	Exon 13 of 13	5		ENSP00000476364.2
LARGE1	ENST00000608642.6	c.*1003A>G		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000476866.2
LARGE1	ENST00000609799.6	c.*1003A>G		3_prime_UTR_variant	Exon 11 of 11	5		ENSP00000476415.2

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64715 AN: 151872 Hom.: 14128 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.430

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.426 AC: 64779 AN: 151992 Hom.: 14147 Cov.: 32 AF XY: 0.420 AC XY: 31211 AN XY: 74294

African (AFR) AF: 0.437 AC: 18128 AN: 41440

American (AMR) AF: 0.394 AC: 6013 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1450 AN: 3466

East Asian (EAS) AF: 0.155 AC: 803 AN: 5182

South Asian (SAS) AF: 0.314 AC: 1511 AN: 4816

European-Finnish (FIN) AF: 0.422 AC: 4454 AN: 10560

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

European-Non Finnish (NFE) AF: 0.453 AC: 30788 AN: 67948

Other (OTH) AF: 0.425 AC: 896 AN: 2108

Alfa AF: 0.446 Hom.: 41482

Bravo AF: 0.432

Asia WGS AF: 0.249 AC: 868 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.18
DANN	Benign	0.58
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs743793; hg19: chr22-33561746;