rs144150303

Variant names:

• chr22-33273631-G-A
• rs144150303
• NM_133642.5:c.*796C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_133642.5(LARGE1):​c.*796C>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 0.000516 in 398,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.207
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-33273631-G-A is Benign according to our data. Variant chr22-33273631-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 341420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00048 (73/152242) while in subpopulation EAS AF = 0.012 (62/5186). AF 95% confidence interval is 0.00957. There are 1 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.*796C>T		3_prime_UTR	Exon 15 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.*796C>T		3_prime_UTR	Exon 16 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.*796C>T		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.*796C>T		3_prime_UTR	Exon 15 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.*796C>T		3_prime_UTR	Exon 16 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.*796C>T		3_prime_UTR	Exon 14 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152124 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000539 AC: 133 AN: 246622 Hom.: 0 Cov.: 0 AF XY: 0.000528 AC XY: 66 AN XY: 125010

African (AFR) AF: 0.00 AC: 0 AN: 7186

American (AMR) AF: 0.00 AC: 0 AN: 7442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9242

East Asian (EAS) AF: 0.00454 AC: 104 AN: 22898

South Asian (SAS) AF: 0.00 AC: 0 AN: 3036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158312

Other (OTH) AF: 0.00177 AC: 29 AN: 16380

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152242 Hom.: 1 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.000393 AC: 6 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000250 Hom.: 1

Bravo AF: 0.000408

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	2.1
DANN	Benign	0.76
PhyloP100		0.21

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: rs144150303; hg19: chr22-33669617;