rs143393575

Positions:

• chr2-71598661-C-A
• chr2-71598661-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000410020.8(DYSF):​c.3672C>A​(p.Tyr1224Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y1224Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF ENST00000410020.8 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -2.29

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 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 2-71598661-C-A is Pathogenic according to our data. Variant chr2-71598661-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 983964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.3672C>A	p.Tyr1224Ter	stop_gained	33/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3618C>A	p.Tyr1206Ter	stop_gained	33/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.3672C>A	p.Tyr1224Ter	stop_gained	33/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.3618C>A	p.Tyr1206Ter	stop_gained	33/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 25, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 22, 2019

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.20	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
Vest4		0.93
GERP RS		-9.7

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: rs143393575; hg19: chr2-71825791;