rs200970855

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001130987.2(DYSF):c.559G>A(p.Gly187Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000281 in 1,613,876 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G187G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00061 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.71

Publications

8 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.063043684).

BP6

Variant 2-71513721-G-A is Benign according to our data. Variant chr2-71513721-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285148.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000611 (93/152310) while in subpopulation AMR AF = 0.00451 (69/15304). AF 95% confidence interval is 0.00365. There are 1 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.559G>A	p.Gly187Arg	missense_variant	Exon 7 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.463G>A	p.Gly155Arg	missense_variant	Exon 6 of 55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.559G>A	p.Gly187Arg	missense_variant	Exon 7 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.463G>A	p.Gly155Arg	missense_variant	Exon 6 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000327

AC:

AN:

250818

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000247

AC:

361

AN:

1461566

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33474

American (AMR)

AF:

0.00114

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000708

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.000246

AC:

274

AN:

1111888

Other (OTH)

AF:

0.000481

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000611

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.00451

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000266

Hom.:

Bravo

AF:

0.000699

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Oct 18, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24838345, 26077850, 18853459, 25312915) -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Jan 23, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;.;.;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.044

MetaRNN

Benign

0.063

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

0.90

.;.;L;.;L;.;.;.;.;.;.

PhyloP100

3.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.033

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

Sift4G

Uncertain

0.031

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

Polyphen

0.90

P;D;P;D;P;D;P;P;P;D;P

Vest4

0.30

MutPred

0.76

.;.;Gain of solvent accessibility (P = 0.019);.;Gain of solvent accessibility (P = 0.019);.;.;.;.;.;.;

MVP

0.86

MPC

0.49

ClinPred

0.044

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.36

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over