rs760443264

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_001130987.2(DYSF):c.3169C>T(p.Arg1057Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1057Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 1.12

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001130987.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-71570683-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1491619.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 2-71570682-C-T is Pathogenic according to our data. Variant chr2-71570682-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282449.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=1}. Variant chr2-71570682-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.3169C>T	p.Arg1057Trp	missense_variant	29/56	ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.3115C>T	p.Arg1039Trp	missense_variant	29/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.3169C>T	p.Arg1057Trp	missense_variant	29/56	1	NM_001130987.2	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3115C>T	p.Arg1039Trp	missense_variant	29/55	1	NM_003494.4	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250656

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135630

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	Observed in a patient with limb-girdle muscular dystrophy who harbored two additional DYSF variants, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Jin et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27647186, 31268554) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 20, 2023	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 02, 2017	- -

Miyoshi muscular dystrophy 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 27, 2023

- -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1039 of the DYSF protein (p.Arg1039Trp). This variant is present in population databases (rs760443264, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of dysferlinopathy and/or DYSF-related conditions (PMID: 27647186, 31268554). ClinVar contains an entry for this variant (Variation ID: 282449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. This variant disrupts the p.Arg1039 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17070050; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

Cadd

Benign

Dann

Pathogenic

1.0

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.075

FATHMM_MKL

Benign

0.55

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

0.99

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.3

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

REVEL

Pathogenic

0.72

Sift

Benign

0.055

T;D;T;D;T;D;D;D;T;D;T

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.81

MutPred

0.78

.;.;Loss of disorder (P = 0.0033);.;Loss of disorder (P = 0.0033);.;.;.;.;.;.;

MVP

0.95

MPC

0.63

ClinPred

0.95

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over