dbSNP rs743793: LARGE1:c.*1003A>G (chr22-33165760-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000610186.6(LARGE1):c.*1003A>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 0.426 in 151,992 control chromosomes in the GnomAD database, including 14,147 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 14147 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

LARGE1
ENST00000610186.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.26

Publications

5 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:

ENSG00000232073 (HGNC:58379):

ENSG00000232073 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
LARGE1	XM_024452302.2 link	c.*1003A>G	3_prime_UTR_variant	Exon 15 of 15	XP_024308070.1
LARGE1	XM_047441606.1 link	c.*1003A>G	3_prime_UTR_variant	Exon 10 of 10	XP_047297562.1
LARGE1	XR_002958722.2 link	n.2638+876A>G	intron_variant	Intron 14 of 14

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
LARGE1	ENST00000610186.6 link	c.*1003A>G	3_prime_UTR_variant	Exon 13 of 13	5	ENSP00000476364.2	V9GY39
LARGE1	ENST00000608642.6 link	c.*1003A>G	3_prime_UTR_variant	Exon 12 of 12	5	ENSP00000476866.2	V9GYK8
LARGE1	ENST00000609799.6 link	c.*1003A>G	3_prime_UTR_variant	Exon 11 of 11	5	ENSP00000476415.2	V9GY56

Frequencies

GnomAD3 genomes

AF:

0.426

AC:

64715

AN:

151872

Hom.:

14128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.437

Gnomad AMI

AF:

0.657

Gnomad AMR

AF:

0.394

Gnomad ASJ

AF:

0.418

Gnomad EAS

AF:

0.155

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.422

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.453

Gnomad OTH

AF:

0.430

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.426

AC:

64779

AN:

151992

Hom.:

14147

Cov.:

AF XY:

0.420

AC XY:

31211

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.437

AC:

18128

AN:

41440

American (AMR)

AF:

0.394

AC:

6013

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.418

AC:

1450

AN:

3466

East Asian (EAS)

AF:

0.155

AC:

803

AN:

5182

South Asian (SAS)

AF:

0.314

AC:

1511

AN:

4816

European-Finnish (FIN)

AF:

0.422

AC:

4454

AN:

10560

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.453

AC:

30788

AN:

67948

Other (OTH)

AF:

0.425

AC:

896

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1860

3719

5579

7438

9298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

590

1180

1770

2360

2950

<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:

0.446

Hom.:

41482

Bravo

AF:

0.432

Asia WGS

AF:

0.249

AC:

868

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.18

(source)

DANN

Benign

0.58

PhyloP100

-1.3

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over