2-71454015-T-A

Position:

• chr2-71454015-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_003494.4(DYSF):​c.17T>A​(p.Ile6Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: DYSF NM_003494.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.15

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]

ENSG00000289327 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain C2 1 (size 100) in uniprot entity DYSF_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003494.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_003494.4	c.17T>A	p.Ile6Asn	missense_variant	1/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.17T>A	p.Ile6Asn	missense_variant	1/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727228

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: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 20, 2019	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Qualitative or quantitative defects of dysferlin Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 6 of the DYSF protein (p.Ile6Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 502095). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	.;.;.;.;D
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.0	M;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.62	P;P;P;P;P
Vest4		0.68
MVP		0.69
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.95

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: rs1354334539; hg19: chr2-71681145;