NM_133642.5:c.1483T>C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_133642.5(LARGE1):c.1483T>C(p.Trp495Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LARGE1
NM_133642.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.67

Publications

4 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 22-33304476-A-G is Pathogenic according to our data. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33304476-A-G is described in CliVar as Pathogenic. Clinvar id is 6219.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5 link	c.1483T>C	p.Trp495Arg	missense_variant	Exon 12 of 15	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.1483T>C	p.Trp495Arg	missense_variant	Exon 12 of 15	5	NM_133642.5	ENSP00000380549.2		O95461-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.00

AC:

AN:

85874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5298

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109556

Other (OTH)

AF:

0.00

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

Pathogenic:1

May 26, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;.;D;D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;.;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.58

PhyloP100

8.7

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-14

.;.;D;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

.;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;.;D;D;D

Vest4

1.0, 1.0, 1.0

MutPred

0.87

.;.;Loss of catalytic residue at P498 (P = 0.0252);Loss of catalytic residue at P498 (P = 0.0252);.;

MVP

0.94

MPC

1.9

ClinPred

1.0

GERP RS

5.3

Varity_R

0.99

gMVP

0.95

Mutation Taster

=1/99

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over