22-33277024-G-A

Variant names:

• chr22-33277024-G-A
• rs41302579
• NM_133642.5:c.2073+36C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133642.5(LARGE1):​c.2073+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,600,152 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (112 hom.)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.507
• 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 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=-0.83).
• BP6: Variant 22-33277024-G-A is Benign according to our data. Variant chr22-33277024-G-A is described in ClinVar as Benign. ClinVar VariationId is 158806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0089 (1355/152194) while in subpopulation NFE AF = 0.0128 (870/67998). AF 95% confidence interval is 0.0121. There are 9 homozygotes in GnomAd4. There are 664 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	NM_133642.5	MANE Select	c.2073+36C>T		intron	N/A	NP_598397.1
	LARGE1	NM_001362949.2		c.2073+36C>T		intron	N/A	NP_001349878.1
	LARGE1	NM_001362951.2		c.2073+36C>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.2073+36C>T		intron	N/A	ENSP00000380549.2
	LARGE1	ENST00000354992.7	TSL:1	c.2073+36C>T		intron	N/A	ENSP00000347088.2
	LARGE1	ENST00000402320.6	TSL:1	c.1917+36C>T		intron	N/A	ENSP00000385223.1

Frequencies

GnomAD3 genomes AF: 0.00889 AC: 1352 AN: 152076 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00904 AC: 2266 AN: 250560 AF XY: 0.00928

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00668

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0110 AC: 15862 AN: 1447958 Hom.: 112 Cov.: 29 AF XY: 0.0109 AC XY: 7856 AN XY: 721128

African (AFR) AF: 0.00202 AC: 67 AN: 33178

American (AMR) AF: 0.00709 AC: 317 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 766 AN: 26060

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39638

South Asian (SAS) AF: 0.00750 AC: 645 AN: 86020

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53336

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5754

European-Non Finnish (NFE) AF: 0.0120 AC: 13194 AN: 1099344

Other (OTH) AF: 0.0111 AC: 665 AN: 59924

GnomAD4 genome AF: 0.00890 AC: 1355 AN: 152194 Hom.: 9 Cov.: 33 AF XY: 0.00892 AC XY: 664 AN XY: 74400

African (AFR) AF: 0.00253 AC: 105 AN: 41548

American (AMR) AF: 0.0113 AC: 173 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4820

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10574

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 870 AN: 67998

Other (OTH) AF: 0.0128 AC: 27 AN: 2108

Alfa AF: 0.0132 Hom.: 3

Bravo AF: 0.00953

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.43
DANN	Benign	0.51
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs41302579; hg19: chr22-33673010;