NM_133642.5:c.*1235A>G

Variant names:

• chr22-33273192-T-C
• rs1801820
• NM_133642.5:c.*1235A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_133642.5(LARGE1):​c.*1235A>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 0.00268 in 389,310 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.19
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 22-33273192-T-C is Benign according to our data. Variant chr22-33273192-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 341411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00533 (812/152322) while in subpopulation AFR AF = 0.0183 (760/41584). AF 95% confidence interval is 0.0172. There are 11 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.*1235A>G		3_prime_UTR	Exon 15 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.*1235A>G		3_prime_UTR	Exon 16 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.*1235A>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.*1235A>G		3_prime_UTR	Exon 15 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.*1235A>G		3_prime_UTR	Exon 16 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.*1235A>G		3_prime_UTR	Exon 14 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152204 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000971 AC: 230 AN: 236988 Hom.: 1 Cov.: 0 AF XY: 0.000840 AC XY: 101 AN XY: 120246

African (AFR) AF: 0.0165 AC: 115 AN: 6962

American (AMR) AF: 0.00182 AC: 13 AN: 7146

Ashkenazi Jewish (ASJ) AF: 0.00594 AC: 53 AN: 8920

East Asian (EAS) AF: 0.00 AC: 0 AN: 22104

South Asian (SAS) AF: 0.00 AC: 0 AN: 2104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20244

Middle Eastern (MID) AF: 0.00161 AC: 2 AN: 1246

European-Non Finnish (NFE) AF: 0.000138 AC: 21 AN: 152554

Other (OTH) AF: 0.00166 AC: 26 AN: 15708

GnomAD4 genome AF: 0.00533 AC: 812 AN: 152322 Hom.: 11 Cov.: 32 AF XY: 0.00502 AC XY: 374 AN XY: 74486

African (AFR) AF: 0.0183 AC: 760 AN: 41584

American (AMR) AF: 0.00131 AC: 20 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00225 Hom.: 0

Bravo AF: 0.00562

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

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	-0.24
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism

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: rs1801820; hg19: chr22-33669178;