rs34671418

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.2500A>G variant in DYSF, which is also known as NM_001130987.2: c.2554A>G p.(Ile852Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 834 (p.Ile834Val). The filtering allele frequency of the variant is 0.08367 for African/African American genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1541/31380), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0, which suggests it does not impact splicing and is below the LGMD VCEP threshold of ≤0.05. The computational predictor REVEL gives a score of 0.08, which is below the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1) (BP4). 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147734/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.041 ( 191 hom., cov: 33)

Exomes 𝑓: 0.024 ( 575 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: 2.92

Publications

13 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 -9 ACMG points.

BP4

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

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.2554A>G	p.Ile852Val	missense_variant	Exon 24 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.2500A>G	p.Ile834Val	missense_variant	Exon 24 of 55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.2554A>G	p.Ile852Val	missense_variant	Exon 24 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.2500A>G	p.Ile834Val	missense_variant	Exon 24 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0406

AC:

6172

AN:

152184

Hom.:

190

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0852

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0184

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0272

Gnomad OTH

AF:

0.0253

GnomAD2 exomes

AF:

0.0232

AC:

5833

AN:

251470

AF XY:

0.0216

show subpopulations

Gnomad AFR exome

AF:

0.0855

Gnomad AMR exome

AF:

0.00948

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0268

Gnomad OTH exome

AF:

0.0204

GnomAD4 exome

AF:

0.0241

AC:

35283

AN:

1461878

Hom.:

575

Cov.:

AF XY:

0.0232

AC XY:

16867

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0882

AC:

2953

AN:

33480

American (AMR)

AF:

0.0106

AC:

476

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0263

AC:

687

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000406

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0325

AC:

1734

AN:

53416

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0251

AC:

27922

AN:

1112000

Other (OTH)

AF:

0.0235

AC:

1421

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2130

4259

6389

8518

10648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1038

2076

3114

4152

5190

<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:

0.0407

AC:

6198

AN:

152302

Hom.:

191

Cov.:

AF XY:

0.0401

AC XY:

2985

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0856

AC:

3555

AN:

41554

American (AMR)

AF:

0.0184

AC:

281

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0364

AC:

387

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0272

AC:

1849

AN:

68014

Other (OTH)

AF:

0.0251

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

311

623

934

1246

1557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0298

Hom.:

253

Bravo

AF:

0.0400

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.0819

AC:

361

ESP6500EA

AF:

0.0230

AC:

198

ExAC

AF:

0.0258

AC:

3132

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0242

EpiControl

AF:

0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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. -

Feb 02, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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.2500A>G variant in DYSF, which is also known as NM_001130987.2: c.2554A>G p.(Ile852Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 834 (p.Ile834Val). The filtering allele frequency of the variant is 0.08367 for African/African American genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1541/31380), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0, which suggests it does not impact splicing and is below the LGMD VCEP threshold of ≤0.05. The computational predictor REVEL gives a score of 0.08, which is below the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1) (BP4). 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, BP4. -

Limb-girdle muscular dystrophy, recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Miyoshi myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.21

.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.93

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

MetaRNN

Benign

0.0033

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

.;.;N;.;N;.;.;.;.;.;.

PhyloP100

2.9

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.34

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.077

Sift

Benign

0.26

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

Sift4G

Benign

0.35

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

Polyphen

0.050

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.21

MPC

0.13

ClinPred

0.0065

GERP RS

2.4

Varity_R

0.033

gMVP

0.28

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over