rs1553518141

chr2-71503275-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001130987.2(DYSF):c.301A>G(p.Ser101Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain C2 1 (size 100) in uniprot entity DYSF_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34130645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.301A>G	p.Ser101Gly	missense_variant	4/56	ENST00000410020.8
DYSF	NM_003494.4	c.298A>G	p.Ser100Gly	missense_variant	4/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.301A>G	p.Ser101Gly	missense_variant	4/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.298A>G	p.Ser100Gly	missense_variant	4/55	1	NM_003494.4	A1

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

Oct 01, 2016

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DYSF-related disease. This sequence change replaces serine with glycine at codon 100 of the DYSF protein (p.Ser100Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.084
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.4	L;L;L;L;L;.;.;.;.;.;.
MutationTaster	Benign	0.84	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.046	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.22	B;B;P;B;B;B;B;B;B;B;B
Vest4		0.69
MutPred		0.33		Loss of stability (P = 0.0239);Loss of stability (P = 0.0239);Loss of stability (P = 0.0239);Loss of stability (P = 0.0239);Loss of stability (P = 0.0239);.;.;.;.;.;.;
MVP		0.73
MPC		0.27
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.36
gMVP		0.29

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: rs1553518141; hg19: chr2-71730405;