rs5998941

Variant names:

• chr22-33433010-G-A
• rs5998941
• NM_133642.5:c.788-745C>T

Variant summary

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

The NM_004737.7(LARGE1):​c.788-745C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 152,016 control chromosomes in the GnomAD database, including 25,061 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 0.56 (25061 hom., cov: 32)
• Consequence: LARGE1 NM_004737.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004737.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	NM_133642.5	MANE Select	c.788-745C>T		intron	N/A	NP_598397.1
	LARGE1	NM_001362949.2		c.788-745C>T		intron	N/A	NP_001349878.1
	LARGE1	NM_001362951.2		c.788-745C>T		intron	N/A	NP_001349880.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.788-745C>T		intron	N/A	ENSP00000380549.2
	LARGE1	ENST00000354992.7	TSL:1	c.788-745C>T		intron	N/A	ENSP00000347088.2
	LARGE1	ENST00000402320.6	TSL:1	c.788-745C>T		intron	N/A	ENSP00000385223.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85700 AN: 151896 Hom.: 25021 Cov.: 32

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.516

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

GnomAD4 genome AF: 0.564 AC: 85794 AN: 152016 Hom.: 25061 Cov.: 32 AF XY: 0.562 AC XY: 41781 AN XY: 74288

African (AFR) AF: 0.713 AC: 29593 AN: 41494

American (AMR) AF: 0.550 AC: 8389 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1443 AN: 3466

East Asian (EAS) AF: 0.311 AC: 1602 AN: 5156

South Asian (SAS) AF: 0.424 AC: 2041 AN: 4814

European-Finnish (FIN) AF: 0.558 AC: 5892 AN: 10554

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35185 AN: 67952

Other (OTH) AF: 0.511 AC: 1079 AN: 2110

Alfa AF: 0.524 Hom.: 28138

Bravo AF: 0.569

Asia WGS AF: 0.366 AC: 1270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.0
DANN	Benign	0.64
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

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: rs5998941; hg19: chr22-33828996;