Genetic Variant DYSF:c.1276+5G>A (chr2-71526351-G-A) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2_SupportingPM3PP4_StrongPVS1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1180+5G>A variant in DYSF, which is also known as NM_001130987.2: c.1276+5G>A, occurs within the splice donor region of intron 12 and has a SpliceAI score of 0.87 for donor loss and 0.44 for gain of an alternative donor. RNAseq analysis has demonstrated abnormal splicing due to this variant, which resulted in either an insertion of 28bp or a deletion of 28bp. Both events led to a frameshift and premature truncation: p.(Met394SerfsTer27) and p.(Val385TrpfsTer5) (PMID:36983702; PVS1_RNA). This variant has been reported in at least nine individuals with dysferlinopathy (PMID:18853459, 25574751, 27647186, 28403181, 32400077, 36983702), including in unknown phase with a pathogenic variant in at least two patients (c.3112C>T p.(Arg1038Ter), 0.5 pts, PMID:36983702; c.6124C>T p.(Arg2042Cys), 0.5 pts, PMID:25574751) and in a homozygous state in one individual (0.5 pts, PMID:27647186, 28403181) (PM3). At least one patient with this variant displayed progressive muscle weakness and reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID:18853459, 25574751, 28403181, 36983702; PP4_Strong). The filtering allele frequency of this variant is 0.000028265 (the upper threshold of the 95% CI of 22/1111436 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic 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; 04/03/2025): PVS1_RNA, PM3, PP4_Strong, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1705673/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 splice_region, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 9.64

Publications

6 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: Pathogenic. The variant received 15 ACMG points.

PVS1

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

PM2

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

PM3

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

PP4

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

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.1276+5G>A	splice_region intron	N/A	NP_001124459.1
DYSF	NM_003494.4	MANE Plus Clinical	c.1180+5G>A	splice_region intron	N/A	NP_003485.1
DYSF	NM_001130981.2		c.1273+5G>A	splice_region intron	N/A	NP_001124453.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1276+5G>A	splice_region intron	N/A	ENSP00000386881.3
DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1180+5G>A	splice_region intron	N/A	ENSP00000258104.3
DYSF	ENST00000409582.7	TSL:1	c.1273+5G>A	splice_region intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248972

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461000

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111436

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal recessive limb-girdle muscular dystrophy (1)

Autosomal recessive limb-girdle muscular dystrophy type 2B (1)

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 (1)

DYSF-related disorder (1)

Miyoshi muscular dystrophy 1 (1)

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

9.6

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.86

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.44

Position offset: -33

DS_DL_spliceai

0.86

Position offset: -5

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