2-71590212-T-A

Position:

chr2-71590212-T-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001130987.2(DYSF):c.3498T>A(p.Tyr1166*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 stop_gained, splice_region

Scores

Splicing: ADA: 0.001773

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.339

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:

DYSF (HGNC:):

DYSF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-71590212-T-A is Pathogenic according to our data. Variant chr2-71590212-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 283206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71590212-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.3498T>A	p.Tyr1166*	stop_gained, splice_region_variant	32/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.3444T>A	p.Tyr1148*	stop_gained, splice_region_variant	32/55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.3498T>A	p.Tyr1166*	stop_gained, splice_region_variant	32/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3444T>A	p.Tyr1148*	stop_gained, splice_region_variant	32/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251462

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727244

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:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Qualitative or quantitative defects of dysferlin

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous p.Tyr1166Ter variant in DYSF was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 6684), in one individual with limb-girdle muscular dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 6684), however the phase of these variants are unknown at this time. The p.Tyr1166Ter variant in DYSF has not been previously reported in individuals with limb-girdle muscular dystrophy 2 but has been identified in 0.005% (2/41402) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758944159). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 283206) and has been interpreted as pathogenic by Eurofins NTD LLC and as likely pathogenic by Illumina Laboratory Services. This nonsense variant leads to a premature termination codon at position 1166, which is predicted to lead to a truncated or absent protein. Loss of function of the DYSF gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy 2. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy 2. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The DYSF c.3444T>A (p.Tyr1148Ter) stop-gained variant has not been reported in the literature; however variants that are predicted to have the same functional consequence as the c.3444T>A (p.Tyr1148Ter) variant have been associated with DYSF-related disorders including limb-girdle muscular dystrophy (LGMD) and Miyoshi myopathy (MM). Three studies have been published in which the p.Tyr1148Ter variant is found in a total of five individuals including two in a homozygous state and three in a compound heterozygous state (Kawabe et al. 2004; Klinge et al. 2010; Dominov et al. 2014). Kawabe et al. (2004) identified two related individuals, one with LGMD and one with MM who were homozygous for a DYSF c.3817-8TG>AA (p. Tyr1148Ter) variant. Klinge et al. (2010) identified an individual with MM who was compound heterozygous for a DYSF c.3444_3445delinsAA (p.Tyr1148Ter) variant and a second missense variant. Dominov et al. (2014) observed a DYSF c.3444_3445delTGinsAA (p.Tyr1148Ter) variant in two siblings with MM who were compound heterozygous for the variant and a second insertion variant. The c.3817-8TG>AA (p. Tyr1148Ter) variant was absent from 120 ethnically matched controls (Kawabe et al. 2004). Control data are unavailable for the c.3444T>A (p.Tyr1148Ter) variant and the c.3444_3445delinsAA (p.Tyr1148Ter) variant. The c.3444T>A (p.Tyr1148Ter) variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the evidence, the c.3444T>A (p.Tyr1148Ter) variant is classified as likely pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.031

FATHMM_MKL

Benign

0.75

Vest4

0.90

GERP RS

-5.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0018

dbscSNV1_RF

Benign

0.53

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.31

Position offset: 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