dbSNP rs201209494: DYSF:p.Thr955Asn (chr2-71568338-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001130987.2(DYSF):c.2864C>A(p.Thr955Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense, splice_region

Scores

Splicing: ADA: 0.8261

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.74

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.2864C>A	p.Thr955Asn	missense_variant, splice_region_variant	Exon 26 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.2810C>A	p.Thr937Asn	missense_variant, splice_region_variant	Exon 26 of 55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.2864C>A	p.Thr955Asn	missense_variant, splice_region_variant	Exon 26 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.2810C>A	p.Thr937Asn	missense_variant, splice_region_variant	Exon 26 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727072

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;.;.;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

T;T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.85

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

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.1

.;.;M;.;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.037

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

Polyphen

0.99

D;D;D;D;D;D;D;P;D;D;D

Vest4

0.90

MutPred

0.30

.;.;Gain of sheet (P = 0.0061);.;Gain of sheet (P = 0.0061);.;.;.;.;.;.;

MVP

0.89

MPC

0.57

ClinPred

0.94

GERP RS

5.0

Varity_R

0.29

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Benign

0.56

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over