10-93313031-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_013451.4(MYOF):c.5878C>T(p.Arg1960Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,609,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1960H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MYOF NM_013451.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

Genes affected

MYOF (HGNC:3656): (myoferlin) Mutations in dysferlin, a protein associated with the plasma membrane, can cause muscle weakness that affects both proximal and distal muscles. The protein encoded by this gene is a type II membrane protein that is structurally similar to dysferlin. It is a member of the ferlin family and associates with both plasma and nuclear membranes. The protein contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. Two transcript variants encoding different isoforms have been found for this gene. Other possible variants have been detected, but their full-length nature has not been determined. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24200785).
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOF	NM_013451.4	c.5878C>T	p.Arg1960Cys	missense_variant	51/54	ENST00000359263.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOF	ENST00000359263.9	c.5878C>T	p.Arg1960Cys	missense_variant	51/54	1	NM_013451.4	P1
MYOF	ENST00000358334.9	c.5839C>T	p.Arg1947Cys	missense_variant	50/53	1
MYOF	ENST00000463743.5	c.*437C>T		3_prime_UTR_variant, NMD_transcript_variant	31/34	5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 44 AN: 245352 Hom.: 0 AF XY: 0.000225 AC XY: 30 AN XY: 133084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000126 AC: 183 AN: 1457000 Hom.: 0 Cov.: 29 AF XY: 0.000153 AC XY: 111 AN XY: 724590

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.0000455

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74452

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.5878C>T (p.R1960C) alteration is located in exon 51 (coding exon 51) of the MYOF gene. This alteration results from a C to T substitution at nucleotide position 5878, causing the arginine (R) at amino acid position 1960 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.56	D
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.73
MVP		0.90
MPC		0.21
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.29
gMVP		0.77

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: rs374294319; hg19: chr10-95072788; COSMIC: COSV63705621;