rs987640

chr22-33163522-T-Achr22-33163522-T-Cchr22-33163522-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000610186.6(LARGE1):c.*3241A>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 0.465 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 ENST00000610186.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
LARGE1	XM_024452302.2	c.*3241A>T		3_prime_UTR_variant	15/15
LARGE1	XM_047441606.1	c.*3241A>T		3_prime_UTR_variant	10/10
LARGE1	XR_002958722.2	n.3481A>T		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000608642.6	c.*3241A>T		3_prime_UTR_variant	12/12	5
LARGE1	ENST00000609799.6	c.*3241A>T		3_prime_UTR_variant	11/11	5
LARGE1	ENST00000610186.6	c.*3241A>T		3_prime_UTR_variant	13/13	5

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

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

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

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.689

Gnomad4 FIN AF: 0.472

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.451

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs987640; hg19: chr22-33559508;