rs61740288

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1369G>A variant in DYSF, which is also known as NM_001130987.2: c.1465G>A (p.Glu489Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 457 (p.Glu457Lys). The filtering allele frequency of the variant is 0.02368 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 4291/251472), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.28 and the computational predictor REVEL gives a score of 0.41. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147721/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.017 ( 30 hom., cov: 31)

Exomes 𝑓: 0.020 ( 372 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: 8.91

Publications

18 publications found

Variant links:

Genes affected

DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

DYSF Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuromuscular disease caused by qualitative or quantitative defects of dysferlin
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
autosomal recessive limb-girdle muscular dystrophy type 2B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
distal myopathy with anterior tibial onset
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy, Paradas type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Miyoshi myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYSF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.1465G>A	p.Glu489Lys	missense_variant	Exon 16 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 link	c.1369G>A	p.Glu457Lys	missense_variant	Exon 15 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.1465G>A	p.Glu489Lys	missense_variant	Exon 16 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8 link	c.1369G>A	p.Glu457Lys	missense_variant	Exon 15 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2611

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.0314

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.0171

AC:

4291

AN:

251472

AF XY:

0.0174

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.00847

Gnomad ASJ exome

AF:

0.0274

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0255

Gnomad NFE exome

AF:

0.0244

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0202

AC:

29528

AN:

1461776

Hom.:

372

Cov.:

AF XY:

0.0200

AC XY:

14532

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00323

AC:

108

AN:

33478

American (AMR)

AF:

0.00988

AC:

442

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

769

AN:

26136

East Asian (EAS)

AF:

0.000554

AC:

AN:

39700

South Asian (SAS)

AF:

0.00751

AC:

648

AN:

86258

European-Finnish (FIN)

AF:

0.0237

AC:

1265

AN:

53420

Middle Eastern (MID)

AF:

0.0193

AC:

111

AN:

5766

European-Non Finnish (NFE)

AF:

0.0225

AC:

25024

AN:

1111904

Other (OTH)

AF:

0.0189

AC:

1139

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1673

3346

5020

6693

8366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

884

1768

2652

3536

4420

<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:

0.0171

AC:

2608

AN:

152134

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1261

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00448

AC:

186

AN:

41526

American (AMR)

AF:

0.0146

AC:

223

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

117

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00663

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0314

AC:

331

AN:

10558

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0244

AC:

1657

AN:

67976

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

132

264

395

527

659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0220

Hom.:

159

Bravo

AF:

0.0158

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0245

AC:

211

ExAC

AF:

0.0170

AC:

2065

EpiCase

AF:

0.0267

EpiControl

AF:

0.0273

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 02, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely 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

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25312915, 22995991, 31862442, 20981092, 17698709, 27884173, 21522182, 25214167)

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DYSF: BS1, BS2

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_003494.4: c.1369G>A variant in DYSF, which is also known as NM_001130987.2: c.1465G>A (p.Glu489Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 457 (p.Glu457Lys). The filtering allele frequency of the variant is 0.02368 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 4291/251472), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.28 and the computational predictor REVEL gives a score of 0.41. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1.

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Nov 14, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

.;.;.;.;D;.;.;.;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0098

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.0

.;.;L;.;L;.;.;.;.;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.1

D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.030

D;D;D;D;D;D;D;D;D;D;D

Vest4

0.43

ClinPred

0.030

GERP RS

4.8

Varity_R

0.74

gMVP

0.72

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: -15

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over