chr22-33273506-G-C

Variant names:

• chr22-33273506-G-C
• rs16992034
• NM_133642.5:c.*921C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133642.5(LARGE1):​c.*921C>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 0.0665 in 398,660 control chromosomes in the GnomAD database, including 1,037 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (503 hom., cov: 32)
  • Exomes 𝑓: 0.061 (534 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.103
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-33273506-G-C is Benign according to our data. Variant chr22-33273506-G-C is described in ClinVar as Benign. ClinVar VariationId is 341414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 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.*921C>G		3_prime_UTR	Exon 15 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.*921C>G		3_prime_UTR	Exon 16 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.*921C>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.*921C>G		3_prime_UTR	Exon 15 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.*921C>G		3_prime_UTR	Exon 16 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.*921C>G		3_prime_UTR	Exon 14 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11473 AN: 152128 Hom.: 494 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0696

Gnomad OTH AF: 0.0770

GnomAD4 exome AF: 0.0608 AC: 14990 AN: 246414 Hom.: 534 Cov.: 0 AF XY: 0.0612 AC XY: 7646 AN XY: 124880

African (AFR) AF: 0.108 AC: 775 AN: 7184

American (AMR) AF: 0.0526 AC: 391 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.0800 AC: 739 AN: 9242

East Asian (EAS) AF: 0.0000437 AC: 1 AN: 22896

South Asian (SAS) AF: 0.0218 AC: 66 AN: 3028

European-Finnish (FIN) AF: 0.0468 AC: 974 AN: 20830

Middle Eastern (MID) AF: 0.0688 AC: 89 AN: 1294

European-Non Finnish (NFE) AF: 0.0684 AC: 10821 AN: 158132

Other (OTH) AF: 0.0693 AC: 1134 AN: 16374

GnomAD4 genome AF: 0.0756 AC: 11503 AN: 152246 Hom.: 503 Cov.: 32 AF XY: 0.0714 AC XY: 5314 AN XY: 74458

African (AFR) AF: 0.114 AC: 4720 AN: 41538

American (AMR) AF: 0.0675 AC: 1033 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 303 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4820

European-Finnish (FIN) AF: 0.0350 AC: 372 AN: 10618

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0696 AC: 4734 AN: 68006

Other (OTH) AF: 0.0767 AC: 162 AN: 2112

Alfa AF: 0.0752 Hom.: 82

Bravo AF: 0.0797

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	-	1	Muscular dystrophy-dystroglycanopathy type B6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.59
PhyloP100		0.10
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: rs16992034; hg19: chr22-33669492;