rs41302579

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.507

Publications

1 publications found

Variant links:

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

LARGE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5 link	c.2073+36C>T		intron_variant	Intron 14 of 14	ENST00000397394.8	NP_598397.1	O95461-1X5DR28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8 link	c.2073+36C>T		intron_variant	Intron 14 of 14	5	NM_133642.5	ENSP00000380549.2		O95461-1

Frequencies

GnomAD3 genomes

AF:

0.00889

AC:

1352

AN:

152076

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0109

AC XY:

7856

AN XY:

721128

show subpopulations

African (AFR)

AF:

0.00202

AC:

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:

AN:

39638

South Asian (SAS)

AF:

0.00750

AC:

645

AN:

86020

European-Finnish (FIN)

AF:

0.00174

AC:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

887

1774

2661

3548

4435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

500

1000

1500

2000

2500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00890

AC:

1355

AN:

152194

Hom.:

Cov.:

AF XY:

0.00892

AC XY:

664

AN XY:

74400

show subpopulations

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:

AN:

5180

South Asian (SAS)

AF:

0.00830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0128

AC:

870

AN:

67998

Other (OTH)

AF:

0.0128

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

158

237

316

395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00953

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.43

(source)

DANN

Benign

0.51

PhyloP100

-0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over