rs34997054

Positions:

chr2-71511847-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001130987.2(DYSF):c.386G>A(p.Gly129Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,551,712 control chromosomes in the GnomAD database, including 98 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 0.0041 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 89 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:17

Conservation

PhyloP100: 8.15

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076210797).

BP6

Variant 2-71511847-G-A is Benign according to our data. Variant chr2-71511847-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94311.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Likely_pathogenic=1, Benign=9}. Variant chr2-71511847-G-A is described in Lovd as [Likely_benign]. Variant chr2-71511847-G-A is described in Lovd as [Benign]. Variant chr2-71511847-G-A is described in Lovd as [Pathogenic]. Variant chr2-71511847-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00468 (6545/1399374) while in subpopulation MID AF= 0.0374 (213/5694). AF 95% confidence interval is 0.0333. There are 89 homozygotes in gnomad4_exome. There are 3348 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.386G>A	p.Gly129Glu	missense_variant	5/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.383G>A	p.Gly128Glu	missense_variant	5/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.386G>A	p.Gly129Glu	missense_variant	5/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.383G>A	p.Gly128Glu	missense_variant	5/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

633

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.0597

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00403

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00713

AC:

1118

AN:

156748

Hom.:

AF XY:

0.00750

AC XY:

619

AN XY:

82504

show subpopulations

Gnomad AFR exome

AF:

0.000571

Gnomad AMR exome

AF:

0.00529

Gnomad ASJ exome

AF:

0.0598

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00474

Gnomad FIN exome

AF:

0.000965

Gnomad NFE exome

AF:

0.00491

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.00468

AC:

6545

AN:

1399374

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

3348

AN XY:

690198

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00521

Gnomad4 ASJ exome

AF:

0.0593

Gnomad4 EAS exome

AF:

0.0000839

Gnomad4 SAS exome

AF:

0.00413

Gnomad4 FIN exome

AF:

0.00108

Gnomad4 NFE exome

AF:

0.00346

Gnomad4 OTH exome

AF:

0.00805

GnomAD4 genome

AF:

0.00414

AC:

631

AN:

152338

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

312

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.0597

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00400

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00777

Hom.:

Bravo

AF:

0.00433

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000508

AC:

ESP6500EA

AF:

0.00422

AC:

ExAC

AF:

0.00404

AC:

251

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2016	This 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2022	Variant summary: DYSF c.383G>A (p.Gly128Glu) results in a non-conservative amino acid change located in the Ferlin, first C2 domain (IPR037726) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0071 in 156748 control chromosomes in the gnomAD database, including 21 homozygotes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is benign. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments (benign/likely benign [n=8], uncertain significance [n=2], likely pathogenic [n=1]). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 03, 2016	p.Gly129Glu in exon 5 of DYSF: This variant is not expected to have clinical sig nificance because it has been identified in 1.8% (162/8872) of European chromoso mes, including 3 homozygotes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs34997054). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:4

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 12, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 02, 2020	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DYSF: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jun 18, 2017

- -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Feb 05, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2013

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DYSF-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2019

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

Miyoshi muscular dystrophy 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Qualitative or quantitative defects of dysferlin

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

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

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

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

MetaRNN

Benign

0.0076

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

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.7

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.7

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

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.025

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

0.70

MVP

0.85

MPC

0.40

ClinPred

0.013

GERP RS

4.5

Varity_R

0.43

gMVP

0.42

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