rs149875093

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001130987.2(DYSF):c.1033+43delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,612,022 control chromosomes in the GnomAD database, including 1,994 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 124 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1870 hom. )

Consequence

DYSF
NM_001130987.2 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.204

Publications

1 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 -16 ACMG points.

BP6

Variant 2-71520250-CT-C is Benign according to our data. Variant chr2-71520250-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 259088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DYSF	NM_001130987.2	MANE Select	c.1033+43delT	intron	N/A	NP_001124459.1
DYSF	NM_003494.4	MANE Plus Clinical	c.937+43delT	intron	N/A	NP_003485.1
DYSF	NM_001130981.2		c.1030+43delT	intron	N/A	NP_001124453.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1033+43delT	intron	N/A	ENSP00000386881.3
DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.937+43delT	intron	N/A	ENSP00000258104.3
DYSF	ENST00000409582.7	TSL:1	c.1030+43delT	intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes

AF:

0.0362

AC:

5516

AN:

152172

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0873

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0354

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0387

GnomAD2 exomes

AF:

0.0349

AC:

8774

AN:

251478

AF XY:

0.0359

show subpopulations

Gnomad AFR exome

AF:

0.0242

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.0861

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0171

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0396

GnomAD4 exome

AF:

0.0468

AC:

68387

AN:

1459734

Hom.:

1870

Cov.:

AF XY:

0.0464

AC XY:

33679

AN XY:

726390

show subpopulations

African (AFR)

AF:

0.0204

AC:

681

AN:

33430

American (AMR)

AF:

0.0210

AC:

939

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0887

AC:

2318

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0362

AC:

3125

AN:

86214

European-Finnish (FIN)

AF:

0.0183

AC:

979

AN:

53410

Middle Eastern (MID)

AF:

0.0467

AC:

269

AN:

5762

European-Non Finnish (NFE)

AF:

0.0514

AC:

57086

AN:

1110042

Other (OTH)

AF:

0.0495

AC:

2989

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

3270

6540

9811

13081

16351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2162

4324

6486

8648

10810

<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:

0.0363

AC:

5522

AN:

152288

Hom.:

124

Cov.:

AF XY:

0.0342

AC XY:

2544

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0239

AC:

994

AN:

41556

American (AMR)

AF:

0.0325

AC:

497

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0873

AC:

303

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0350

AC:

169

AN:

4822

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10614

Middle Eastern (MID)

AF:

0.0552

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0478

AC:

3254

AN:

68020

Other (OTH)

AF:

0.0383

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

270

539

809

1078

1348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0248

Hom.:

Bravo

AF:

0.0366

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jun 14, 2018

GeneDx

Significance:Likely 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.20

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over