2-71551073-G-A

Position:

chr2-71551073-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001130987.2(DYSF):c.1609G>A(p.Gly537Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G537W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 10.0

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-71551073-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2819412.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-71551073-G-A is Pathogenic according to our data. Variant chr2-71551073-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71551073-G-A 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.1609G>A	p.Gly537Arg	missense_variant	18/56	ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.1555G>A	p.Gly519Arg	missense_variant	18/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.1609G>A	p.Gly537Arg	missense_variant	18/56	1	NM_001130987.2	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.1555G>A	p.Gly519Arg	missense_variant	18/55	1	NM_003494.4	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	reference population	Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2016	The c.1555 G>A pathogenic variant in the DYSF gene has been previously reported in the homozygous state in two siblings with Miyoshi myopathy and absent dysferlin expression on Western blot. Additionally, it was observed in the heterozygous state in their father with calf myalgias and progressive difficulty with walking (Illa et al., 2007). Functional studies demonstrate the c.1555 G>A variant creates a new splice acceptor site resulting in an out-of-frame deletion of 35 base pairs in exon 18 (De Luna et al., 2007; Kergourlay et al., 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2015	- -

Miyoshi muscular dystrophy 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 17, 2007

- -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 26, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing (PMID:¬†25312915). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be homozygous or in combination with another DYSF variant in individuals affected with distal myopathy (PMID: 17287450,¬†30107846). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6679). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 519 of the DYSF protein (p.Gly519Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

.;.;.;.;D;.;.;.;.;.;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.90

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

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.9

.;.;H;.;H;.;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.2

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

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

0.98

MutPred

0.56

.;.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;.;.;.;.;.;

MVP

0.98

MPC

0.71

ClinPred

1.0

GERP RS

5.3

Varity_R

0.89

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

DS_AL_spliceai

0.48

Position offset: -32

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