rs4821129

Variant names:

• chr22-33099542-G-A
• rs4821129
• ENST00000731026.1:n.287+17065G>A

Variant summary

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

The ENST00000731026.1(LINC01640):​n.287+17065G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,116 control chromosomes in the GnomAD database, including 2,133 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 0.15 (2133 hom., cov: 32)
• Consequence: LINC01640 ENST00000731026.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• Publications: 2 publications found

Genes affected

LINC01640 (HGNC:52427): (long intergenic non-protein coding RNA 1640)

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000731026.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINC01640	ENST00000731026.1		n.287+17065G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22655 AN: 151998 Hom.: 2133 Cov.: 32

Gnomad AFR AF: 0.0661

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.187

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22654 AN: 152116 Hom.: 2133 Cov.: 32 AF XY: 0.149 AC XY: 11104 AN XY: 74362

African (AFR) AF: 0.0660 AC: 2741 AN: 41528

American (AMR) AF: 0.153 AC: 2334 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1056 AN: 3472

East Asian (EAS) AF: 0.407 AC: 2098 AN: 5150

South Asian (SAS) AF: 0.223 AC: 1072 AN: 4802

European-Finnish (FIN) AF: 0.122 AC: 1297 AN: 10588

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11348 AN: 67980

Other (OTH) AF: 0.191 AC: 405 AN: 2116

Alfa AF: 0.157 Hom.: 332

Bravo AF: 0.149

Asia WGS AF: 0.293 AC: 1017 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.49
PhyloP100		-0.79

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4821129;

hg19: chr22-33495528;