rs34997054

Positions:

• chr2-71511847-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:17
• Conservation: PhyloP100: 8.15

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]

ACMG classification

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: {Benign=10, Likely_benign=3, Likely_pathogenic=1}. 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	UniProt
DYSF	NM_001130987.2	c.386G>A	p.Gly129Glu	missense_variant	5/56	ENST00000410020.8
DYSF	NM_003494.4	c.383G>A	p.Gly128Glu	missense_variant	5/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.386G>A	p.Gly129Glu	missense_variant	5/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.383G>A	p.Gly128Glu	missense_variant	5/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 633 AN: 152220 Hom.: 10 Cov.: 33

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.: 21 AF XY: 0.00750 AC XY: 619 AN XY: 82504

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.: 89 Cov.: 31 AF XY: 0.00485 AC XY: 3348 AN XY: 690198

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.: 9 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74494

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.: 13

Bravo AF: 0.00433

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000508 AC: 2

ESP6500EA AF: 0.00422 AC: 32

ExAC AF: 0.00404 AC: 251

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 12, 2017	- -

not provided Benign:3

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)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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, criteria provided, single submitter

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
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	T
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	T
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	T
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

Other links and lift over

dbSNP: rs34997054; hg19: chr2-71738977; COSMIC: COSV105093661;