rs3764971

Positions:

• chr2-71570582-G-A
• chr2-71570582-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.3086-17G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,611,560 control chromosomes in the GnomAD database, including 50,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3894 hom., cov: 33)
  • Exomes 𝑓: 0.25 (46542 hom.)
• Consequence: DYSF NM_001130987.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.455

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-71570582-G-A is Benign according to our data. Variant chr2-71570582-G-A is described in ClinVar as [Benign]. Clinvar id is 94297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71570582-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.3086-17G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3032-17G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.3032-17G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003494.4	ENSP00000258104	A1
DYSF	ENST00000410020.8	c.3086-17G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130987.2	ENSP00000386881	A1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30552 AN: 152062 Hom.: 3888 Cov.: 33

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.205

GnomAD3 exomes AF: 0.259 AC: 63891 AN: 246488 Hom.: 9445 AF XY: 0.266 AC XY: 35443 AN XY: 133372

Gnomad AFR exome AF: 0.0576

Gnomad AMR exome AF: 0.272

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.453

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.245 AC: 357986 AN: 1459380 Hom.: 46542 Cov.: 34 AF XY: 0.249 AC XY: 180587 AN XY: 725894

Gnomad4 AFR exome AF: 0.0559

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.419

Gnomad4 SAS exome AF: 0.381

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.201 AC: 30551 AN: 152180 Hom.: 3894 Cov.: 33 AF XY: 0.209 AC XY: 15561 AN XY: 74394

Gnomad4 AFR AF: 0.0618

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.203

Alfa AF: 0.217 Hom.: 2149

Bravo AF: 0.192

Asia WGS AF: 0.372 AC: 1292 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Distal myopathy with anterior tibial onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Miyoshi muscular dystrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Qualitative or quantitative defects of dysferlin Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.7
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3764971; hg19: chr2-71797712;