NM_001130987.2:c.1931T>C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1877T>C variant in DYSF, which is also known as NM_001130987.2: c.1931T>C p.(Met644Thr), is a missense variant predicted to cause substitution of methionine by threonine at amino acid 626 (p.Met626Thr). The filtering allele frequency of the variant is 0.002276 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 323/251362), which is higher than the VCEP threshold of 0.001 (BS1). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.12, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Likely Benign 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; 01/08/2025): BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1705983/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:6

Conservation

PhyloP100: -0.00800

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_benign. Variant got -4 ACMG points.

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.1931T>C	p.Met644Thr	missense_variant	Exon 20 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.1877T>C	p.Met626Thr	missense_variant	Exon 20 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.1931T>C	p.Met644Thr	missense_variant	Exon 20 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.1877T>C	p.Met626Thr	missense_variant	Exon 20 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

170

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00216

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00128

AC:

323

AN:

251362

Hom.:

AF XY:

0.00130

AC XY:

176

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00188

AC:

2751

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1324

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000582

Gnomad4 NFE exome

AF:

0.00232

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.00112

AC:

170

AN:

152316

Hom.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00216

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00150

AC:

182

EpiCase

AF:

0.00174

EpiControl

AF:

0.00207

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Oct 06, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF: BP4, BS2 -

Jul 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Miyoshi muscular dystrophy 1

Uncertain:1

Feb 22, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Jun 22, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_003494.4: c.1877T>C variant in DYSF, which is also known as NM_001130987.2: c.1931T>C p.(Met644Thr), is a missense variant predicted to cause substitution of methionine by threonine at amino acid 626 (p.Met626Thr). The filtering allele frequency of the variant is 0.002276 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 323/251362), which is higher than the VCEP threshold of 0.001 (BS1). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.12, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Likely Benign 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; 01/08/2025): BS1. -

DYSF-related disorder

Benign:1

Sep 10, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Benign

3.4

DANN

Benign

0.40

DEOGEN2

Benign

0.13

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

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.47

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

M_CAP

Benign

0.0086

MetaRNN

Benign

0.0051

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.5

.;.;N;.;N;.;.;.;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

1.2

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

REVEL

Benign

0.12

Sift

Benign

1.0

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

Sift4G

Benign

0.70

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

Polyphen

0.0

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.054

MVP

0.33

MPC

0.17

ClinPred

0.00096

GERP RS

0.97

Varity_R

0.020

gMVP

0.17

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