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rs7573406

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001130987.2(DYSF):c.4621C>T(p.Leu1541=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00823 in 1,609,458 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0081 ( 7 hom., cov: 33)
Exomes 𝑓: 0.0082 ( 83 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 1.23
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 2-71644058-C-T is Benign according to our data. Variant chr2-71644058-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94325.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=1, Uncertain_significance=3}. Variant chr2-71644058-C-T is described in Lovd as [Benign]. Variant chr2-71644058-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.23 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00824 (12006/1457166) while in subpopulation SAS AF= 0.017 (1447/85088). AF 95% confidence interval is 0.0163. There are 83 homozygotes in gnomad4_exome. There are 6262 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.4621C>T p.Leu1541= synonymous_variant 42/56 ENST00000410020.8
DYSFNM_003494.4 linkuse as main transcriptc.4504C>T p.Leu1502= synonymous_variant 41/55 ENST00000258104.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.4621C>T p.Leu1541= synonymous_variant 42/561 NM_001130987.2 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.4504C>T p.Leu1502= synonymous_variant 41/551 NM_003494.4 A1O75923-1

Frequencies

GnomAD3 genomes
AF:
0.00813
AC:
1237
AN:
152174
Hom.:
7
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00794
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00884
Gnomad ASJ
AF:
0.00720
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.0147
Gnomad FIN
AF:
0.00226
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.00908
Gnomad OTH
AF:
0.0124
GnomAD3 exomes
AF:
0.00791
AC:
1919
AN:
242576
Hom.:
14
AF XY:
0.00878
AC XY:
1148
AN XY:
130704
show subpopulations
Gnomad AFR exome
AF:
0.00751
Gnomad AMR exome
AF:
0.00562
Gnomad ASJ exome
AF:
0.0100
Gnomad EAS exome
AF:
0.0000552
Gnomad SAS exome
AF:
0.0171
Gnomad FIN exome
AF:
0.00247
Gnomad NFE exome
AF:
0.00812
Gnomad OTH exome
AF:
0.0127
GnomAD4 exome
AF:
0.00824
AC:
12006
AN:
1457166
Hom.:
83
Cov.:
32
AF XY:
0.00865
AC XY:
6262
AN XY:
724268
show subpopulations
Gnomad4 AFR exome
AF:
0.00775
Gnomad4 AMR exome
AF:
0.00687
Gnomad4 ASJ exome
AF:
0.00959
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0170
Gnomad4 FIN exome
AF:
0.00354
Gnomad4 NFE exome
AF:
0.00788
Gnomad4 OTH exome
AF:
0.0104
GnomAD4 genome
AF:
0.00815
AC:
1241
AN:
152292
Hom.:
7
Cov.:
33
AF XY:
0.00784
AC XY:
584
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00799
Gnomad4 AMR
AF:
0.00883
Gnomad4 ASJ
AF:
0.00720
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0145
Gnomad4 FIN
AF:
0.00226
Gnomad4 NFE
AF:
0.00908
Gnomad4 OTH
AF:
0.0123
Alfa
AF:
0.00872
Hom.:
3
Bravo
AF:
0.00868
Asia WGS
AF:
0.00549
AC:
19
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 13, 2015p.Leu1541Leu in exon 42 of DYSF: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.8% (34/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7573406). -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-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. -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncApr 22, 2021- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 13, 2013- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 19, 2016This 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. -
Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Limb-Girdle Muscular Dystrophy, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Miyoshi myopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Miyoshi muscular dystrophy 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabMay 18, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
Cadd
Benign
4.2
Dann
Benign
0.50

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

LitVar

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

Other links and lift over

dbSNP: rs7573406; hg19: chr2-71871188; COSMIC: COSV50435908; COSMIC: COSV50435908; API