rs141720146

Positions:

• chr2-71598745-T-A
• chr2-71598745-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001130987.2(DYSF):​c.3756T>A​(p.Tyr1252Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y1252Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 stop_gained, splice_region
• Scores: Splicing: ADA: 0.00005273
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -3.45

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 12 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 2-71598745-T-A is Pathogenic according to our data. Variant chr2-71598745-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 857602.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.3756T>A	p.Tyr1252Ter	stop_gained, splice_region_variant	33/56	ENST00000410020.8
DYSF	NM_003494.4	c.3702T>A	p.Tyr1234Ter	stop_gained, splice_region_variant	33/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.3756T>A	p.Tyr1252Ter	stop_gained, splice_region_variant	33/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.3702T>A	p.Tyr1234Ter	stop_gained, splice_region_variant	33/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 857602). This premature translational stop signal has been observed in individual(s) with Miyoshi myopathy (PMID: 27647186). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1234*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.38	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
Vest4		0.97
GERP RS		-4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.33
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: rs141720146; hg19: chr2-71825875;