rs886044537

Positions:

• chr2-71539239-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_003494.4(DYSF):​c.1480G>T​(p.Glu494Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYSF NM_003494.4 stop_gained, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.03

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 Pathogenic. Variant got 22 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-71539239-G-T is Pathogenic according to our data. Variant chr2-71539239-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 290700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71539239-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.1576G>T	p.Val526Leu	missense_variant, splice_region_variant	17/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1480G>T	p.Glu494Ter	stop_gained, splice_region_variant	16/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.1576G>T	p.Val526Leu	missense_variant, splice_region_variant	17/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.1480G>T	p.Glu494Ter	stop_gained, splice_region_variant	16/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Benign	-0.070
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.052	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;D;D;D;D;D
Vest4		0.87
ClinPred		0.49	T
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.68		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886044537; hg19: chr2-71766369;