rs143059463

Variant names:

• chr2-71664366-C-T
• rs143059463
• NM_001130987.2:c.5102C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_001130987.2(DYSF):​c.5102C>T​(p.Thr1701Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1701T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.90
• Publications: 2 publications found

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]

DYSF Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001130987.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• BP6: Variant 2-71664366-C-T is Benign according to our data. Variant chr2-71664366-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554830.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.5102C>T	p.Thr1701Met	missense	Exon 46 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.4985C>T	p.Thr1662Met	missense	Exon 45 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.5099C>T	p.Thr1700Met	missense	Exon 46 of 56	NP_001124453.1	O75923-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.5102C>T	p.Thr1701Met	missense	Exon 46 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4985C>T	p.Thr1662Met	missense	Exon 45 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.5099C>T	p.Thr1700Met	missense	Exon 46 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251490 AF XY: 0.0000883

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.0000344 AC XY: 25 AN XY: 727246

African (AFR) AF: 0.000418 AC: 14 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1112008

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74460

African (AFR) AF: 0.000409 AC: 17 AN: 41558

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2B (2)
-	1	-	Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 (1)
-	-	1	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.94
MPC		0.66
ClinPred		0.71	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.73
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143059463; hg19: chr2-71891496; COSMIC: COSV50470120;