2-71454023-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003494.4(DYSF):c.25G>A(p.Ala9Thr) variant causes a missense change. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYSF NM_003494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.17

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_003494.4	c.25G>A	p.Ala9Thr	missense_variant	1/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.25G>A	p.Ala9Thr	missense_variant	1/55	1	NM_003494.4	A1
	ENST00000685766.2	n.448C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Qualitative or quantitative defects of dysferlin Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. ClinVar contains an entry for this variant (Variation ID: 2199205). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 9 of the DYSF protein (p.Ala9Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.2	H;H;H;H;H
MutationTaster	Benign	0.94	N;N;N;N;N
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.39
MutPred		0.84		Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);
MVP		0.91
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.92

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: rs887165313; hg19: chr2-71681153;