22-33163522-T-A

Variant names:

• chr22-33163522-T-A
• rs987640
• ENST00000674562.1:n.1154A>T

Variant summary

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

The ENST00000674562.1(LARGE1):​n.1154A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,062 control chromosomes in the GnomAD database, including 16,556 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 0.46 (16556 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: LARGE1 ENST00000674562.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• Publications: 15 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) 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	XR_002958722.2	n.3481A>T		non_coding_transcript_exon_variant	Exon 15 of 15
LARGE1	XR_007067994.1	n.3518A>T		non_coding_transcript_exon_variant	Exon 16 of 16
LARGE1	XM_024452302.2	c.*3241A>T		3_prime_UTR_variant	Exon 15 of 15		XP_024308070.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000674562.1	n.1154A>T		non_coding_transcript_exon_variant	Exon 3 of 3
LARGE1	ENST00000676217.1	n.1143A>T		non_coding_transcript_exon_variant	Exon 3 of 3
LARGE1	ENST00000610186.6	c.*3241A>T		3_prime_UTR_variant	Exon 13 of 13	5		ENSP00000476364.2

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70614 AN: 151940 Hom.: 16547 Cov.: 33

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.451

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

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) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.465 AC: 70663 AN: 152058 Hom.: 16556 Cov.: 33 AF XY: 0.467 AC XY: 34737 AN XY: 74314

African (AFR) AF: 0.449 AC: 18642 AN: 41480

American (AMR) AF: 0.457 AC: 6979 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1421 AN: 3468

East Asian (EAS) AF: 0.474 AC: 2456 AN: 5180

South Asian (SAS) AF: 0.689 AC: 3321 AN: 4820

European-Finnish (FIN) AF: 0.472 AC: 4976 AN: 10552

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.459 AC: 31190 AN: 67964

Other (OTH) AF: 0.451 AC: 953 AN: 2112

Alfa AF: 0.308 Hom.: 747

Bravo AF: 0.460

Asia WGS AF: 0.594 AC: 2064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.55
DANN	Benign	0.71
PhyloP100		-0.060

Splicing

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

Other links and lift over

dbSNP: rs987640; hg19: chr22-33559508;