rs116335813

Variant names:

• chr22-33273687-T-C
• rs116335813
• NM_133642.5:c.*740A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_133642.5(LARGE1):​c.*740A>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 0.0129 in 398,644 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (108 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (36 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.987
• Publications: 1 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

  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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-33273687-T-C is Benign according to our data. Variant chr22-33273687-T-C is described in ClinVar as Benign. ClinVar VariationId is 341422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.06 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133642.5. 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
	LARGE1	NM_133642.5	MANE Select	c.*740A>G		3_prime_UTR	Exon 15 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.*740A>G		3_prime_UTR	Exon 16 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.*740A>G		3_prime_UTR	Exon 15 of 15	NP_001349880.1	O95461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.*740A>G		3_prime_UTR	Exon 15 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.*740A>G		3_prime_UTR	Exon 16 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.*740A>G		3_prime_UTR	Exon 14 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3391 AN: 152088 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.00703 AC: 1732 AN: 246440 Hom.: 36 Cov.: 0 AF XY: 0.00701 AC XY: 876 AN XY: 124888

African (AFR) AF: 0.0645 AC: 463 AN: 7180

American (AMR) AF: 0.0133 AC: 99 AN: 7458

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 127 AN: 9240

East Asian (EAS) AF: 0.000874 AC: 20 AN: 22894

South Asian (SAS) AF: 0.0567 AC: 160 AN: 2824

European-Finnish (FIN) AF: 0.000481 AC: 10 AN: 20800

Middle Eastern (MID) AF: 0.0425 AC: 55 AN: 1294

European-Non Finnish (NFE) AF: 0.00341 AC: 540 AN: 158378

Other (OTH) AF: 0.0158 AC: 258 AN: 16372

GnomAD4 genome AF: 0.0223 AC: 3391 AN: 152204 Hom.: 108 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74416

African (AFR) AF: 0.0620 AC: 2573 AN: 41516

American (AMR) AF: 0.0147 AC: 225 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5188

South Asian (SAS) AF: 0.0556 AC: 268 AN: 4816

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 68010

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.0140 Hom.: 17

Bravo AF: 0.0249

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	-	1	Muscular dystrophy-dystroglycanopathy type B6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.69
PhyloP100		0.99
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: rs116335813; hg19: chr22-33669673;