rs374705038

Positions:

• chr2-71613365-C-A
• chr2-71613365-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130987.2(DYSF):​c.4419C>A​(p.Asp1473Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.10

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06096542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4419C>A	p.Asp1473Glu	missense_variant	40/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4365C>A	p.Asp1455Glu	missense_variant	40/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4419C>A	p.Asp1473Glu	missense_variant	40/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.4365C>A	p.Asp1455Glu	missense_variant	40/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces aspartic acid with glutamic acid at codon 1455 of the DYSF protein (p.Asp1455Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. 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) performed at Invitae indicates that this missense variant is not expected to disrupt DYSF protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.30
DANN	Benign	0.97
DEOGEN2	Benign	0.32	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.061	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.40	.;.;N;.;N;.;.;.;.;.;.
MutationTaster	Benign	0.88	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.070	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0080	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.16
MutPred		0.32		.;.;Gain of catalytic residue at D1455 (P = 0.0436);.;Gain of catalytic residue at D1455 (P = 0.0436);.;.;.;.;.;.;
MVP		0.48
MPC		0.14
ClinPred		0.52	D
GERP RS		-8.4
Varity_R		0.096
gMVP		0.42

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: rs374705038; hg19: chr2-71840495;