dbSNP rs86487: LARGE1:p.Ala145Ala (chr22-33626300-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_133642.5(LARGE1):c.435C>T(p.Ala145Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,612,472 control chromosomes in the GnomAD database, including 194,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A145A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.41 ( 14560 hom., cov: 32)

Exomes 𝑓: 0.49 ( 179913 hom. )

Consequence

LARGE1
NM_133642.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0540

Publications

25 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
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 22-33626300-G-A is Benign according to our data. Variant chr22-33626300-G-A is described in ClinVar as Benign. ClinVar VariationId is 95175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.054 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LARGE1	NM_133642.5	MANE Select	c.435C>T	p.Ala145Ala	synonymous	Exon 4 of 15	NP_598397.1	O95461-1
LARGE1	NM_001362949.2		c.435C>T	p.Ala145Ala	synonymous	Exon 5 of 16	NP_001349878.1	O95461-1
LARGE1	NM_001362951.2		c.435C>T	p.Ala145Ala	synonymous	Exon 4 of 15	NP_001349880.1	O95461-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.435C>T	p.Ala145Ala	synonymous	Exon 4 of 15	ENSP00000380549.2	O95461-1
LARGE1	ENST00000354992.7	TSL:1	c.435C>T	p.Ala145Ala	synonymous	Exon 5 of 16	ENSP00000347088.2	O95461-1
LARGE1	ENST00000402320.6	TSL:1	c.435C>T	p.Ala145Ala	synonymous	Exon 4 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

62024

AN:

151924

Hom.:

14551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.522

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.537

Gnomad EAS

AF:

0.584

Gnomad SAS

AF:

0.518

Gnomad FIN

AF:

0.524

Gnomad MID

AF:

0.528

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.436

GnomAD2 exomes

AF:

0.488

AC:

122435

AN:

251030

AF XY:

0.492

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.542

Gnomad ASJ exome

AF:

0.542

Gnomad EAS exome

AF:

0.572

Gnomad FIN exome

AF:

0.525

Gnomad NFE exome

AF:

0.488

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.492

AC:

718511

AN:

1460430

Hom.:

179913

Cov.:

AF XY:

0.493

AC XY:

358346

AN XY:

726612

show subpopulations

African (AFR)

AF:

0.150

AC:

5036

AN:

33464

American (AMR)

AF:

0.533

AC:

23837

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.542

AC:

14148

AN:

26120

East Asian (EAS)

AF:

0.595

AC:

23609

AN:

39684

South Asian (SAS)

AF:

0.511

AC:

44055

AN:

86204

European-Finnish (FIN)

AF:

0.522

AC:

27873

AN:

53376

Middle Eastern (MID)

AF:

0.527

AC:

3042

AN:

5768

European-Non Finnish (NFE)

AF:

0.493

AC:

547475

AN:

1110782

Other (OTH)

AF:

0.488

AC:

29436

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

20143

40286

60428

80571

100714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16008

32016

48024

64032

80040

<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:

0.408

AC:

62037

AN:

152042

Hom.:

14560

Cov.:

AF XY:

0.411

AC XY:

30510

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.161

AC:

6674

AN:

41494

American (AMR)

AF:

0.497

AC:

7600

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

1864

AN:

3468

East Asian (EAS)

AF:

0.584

AC:

3012

AN:

5156

South Asian (SAS)

AF:

0.518

AC:

2491

AN:

4812

European-Finnish (FIN)

AF:

0.524

AC:

5525

AN:

10542

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.490

AC:

33315

AN:

67972

Other (OTH)

AF:

0.440

AC:

930

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1693

3386

5080

6773

8466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.452

Hom.:

35614

Bravo

AF:

0.398

Asia WGS

AF:

0.518

AC:

1802

AN:

3478

EpiCase

AF:

0.507

EpiControl

AF:

0.506

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Muscular dystrophy-dystroglycanopathy type B6 (2)

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

-0.054

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=93/7

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over