rs62225294

Variant names:

• chr22-33432111-G-A
• rs62225294
• NM_133642.5:c.892+50C>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_004737.7(LARGE1):​c.892+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,421,380 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (34 hom.)
• Consequence: LARGE1 NM_004737.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.720
• Publications: 0 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=-0.91).
• BP6: Variant 22-33432111-G-A is Benign according to our data. Variant chr22-33432111-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95177.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 = 0.00473 (720/152258) while in subpopulation NFE AF = 0.00756 (514/68030). AF 95% confidence interval is 0.00702. There are 0 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004737.7. 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.892+50C>T		intron	N/A	NP_598397.1
	LARGE1	NM_001362949.2		c.892+50C>T		intron	N/A	NP_001349878.1
	LARGE1	NM_001362951.2		c.892+50C>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.892+50C>T		intron	N/A	ENSP00000380549.2
	LARGE1	ENST00000354992.7	TSL:1	c.892+50C>T		intron	N/A	ENSP00000347088.2
	LARGE1	ENST00000402320.6	TSL:1	c.892+50C>T		intron	N/A	ENSP00000385223.1

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 718 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00754

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00477 AC: 1187 AN: 248854 AF XY: 0.00487

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00848

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00294

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00653 AC: 8282 AN: 1269122 Hom.: 34 Cov.: 18 AF XY: 0.00645 AC XY: 4137 AN XY: 641104

African (AFR) AF: 0.00115 AC: 34 AN: 29682

American (AMR) AF: 0.00382 AC: 169 AN: 44284

Ashkenazi Jewish (ASJ) AF: 0.00891 AC: 222 AN: 24922

East Asian (EAS) AF: 0.00 AC: 0 AN: 38770

South Asian (SAS) AF: 0.00231 AC: 190 AN: 82196

European-Finnish (FIN) AF: 0.00295 AC: 157 AN: 53256

Middle Eastern (MID) AF: 0.00446 AC: 24 AN: 5376

European-Non Finnish (NFE) AF: 0.00756 AC: 7083 AN: 936610

Other (OTH) AF: 0.00746 AC: 403 AN: 54026

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74424

African (AFR) AF: 0.00128 AC: 53 AN: 41550

American (AMR) AF: 0.00478 AC: 73 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

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

South Asian (SAS) AF: 0.00312 AC: 15 AN: 4814

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00756 AC: 514 AN: 68030

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00666 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.36
DANN	Benign	0.57
PhyloP100		-0.72
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: rs62225294; hg19: chr22-33828097;