rs753861836

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000410020.8(DYSF):​c.5785-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

DYSF
ENST00000410020.8 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.9974
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.405
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-71674190-G-A is Pathogenic according to our data. Variant chr2-71674190-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 283474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71674190-G-A is described in Lovd as [Pathogenic]. Variant chr2-71674190-G-A is described in Lovd as [Pathogenic]. Variant chr2-71674190-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-71674190-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.5785-7G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000410020.8 NP_001124459.1
DYSFNM_003494.4 linkuse as main transcriptc.5668-7G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000258104.8 NP_003485.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYSFENST00000258104.8 linkuse as main transcriptc.5668-7G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_003494.4 ENSP00000258104 A1O75923-1
DYSFENST00000410020.8 linkuse as main transcriptc.5785-7G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_001130987.2 ENSP00000386881 A1O75923-13

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251410
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135896
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 SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461376
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
727034
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 19, 2017- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 28, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJul 21, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 03, 2023Non-canonical splice site variant demonstrated to result in loss of function (Kergourlay et al., 2014; Izumi et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16100712, 31589614, 34559919, 32400077, 25312915, 25591676, 33610434, 29794729) -
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalNov 11, 2021This sequence change in DYSF is an intronic variant located in intron 50. The highest population minor allele frequency in gnomAD v2.1 is 0.003% (1/30,614 alleles) in the South Asian population, which is consistent with a recessive condition. This variant has been detected in at least 10 individuals with dysferlinopathy. Of those individuals, two individuals were homozygous and eight were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those were confirmed in trans by parental testing. Almost all of these individuals underwent dysferlin expression analysis on muscle biopsies, and demonstrated deficient expression (PMID: 16100712, 18853459, 19528035, 24488599, 32400077, 33927379). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by creating a de novo acceptor splice site in intron 50 of DYSF. This prediction is confirmed by RT-PCR and mini-gene assays. The assays demonstrated that the variant impacts splicing by leading to inclusion of 5 bp from intron 50 (r.5667_5668ins5668-5_5668-1, p.Lys1889insTrpfs*56; PMID: 16100712, 25312915, 32400077). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3, PP4. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 11, 2023Variant summary: DYSF c.5668-7G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant creates a 3' acceptor site. Additionally, three predict the variant weakens the wild-type 3' acceptor site, and one predicts the variant abolishes the wild-type 3' acceptor site. Several publications report experimental evidence supporting these computational predictions, finding that the variant results in the use of a cryptic 3' acceptor site 5 nucleotides upstream of the wild-type site, leading to a frameshift (p.Lys1889insTrpfsX56; e.g., Cagliani_2005, Kergourlay_2014). The variant allele was found at a frequency of 1.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5668-7G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Limb-Girdle Muscular Dystrophy (e.g., Cagliani_2005, Charnay_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16100712, 33927379, 25312915). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 7) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:2
Likely pathogenic, no assertion criteria providedclinical testingCounsylMar 21, 2017- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 27, 2024- -
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023This sequence change falls in intron 50 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein. This variant is present in population databases (rs753861836, gnomAD 0.003%). This variant has been observed in individual(s) with limb-girdle muscular dystrophy type 2B and Miyoshi muscular dystrophy type 1 (PMID: 16100712, 18853459, 19528035, 24488599). ClinVar contains an entry for this variant (Variation ID: 283474). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Uncertain
24
DANN
Benign
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.99
Position offset: 2
DS_AL_spliceai
0.94
Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753861836; hg19: chr2-71901320; API