10-93313135-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013451.4(MYOF):c.5774C>T(p.Pro1925Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: MYOF NM_013451.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019111335).
• BS2: High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOF	NM_013451.4	c.5774C>T	p.Pro1925Leu	missense_variant	51/54	ENST00000359263.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOF	ENST00000359263.9	c.5774C>T	p.Pro1925Leu	missense_variant	51/54	1	NM_013451.4	P1
MYOF	ENST00000358334.9	c.5735C>T	p.Pro1912Leu	missense_variant	50/53	1
MYOF	ENST00000463743.5	c.*333C>T		3_prime_UTR_variant, NMD_transcript_variant	31/34	5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000325 AC: 81 AN: 249440 Hom.: 0 AF XY: 0.000325 AC XY: 44 AN XY: 135334

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000232 AC: 339 AN: 1461784 Hom.: 0 Cov.: 29 AF XY: 0.000232 AC XY: 169 AN XY: 727194

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74480

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

EpiCase AF: 0.000273

EpiControl AF: 0.000178

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

May 04, 2022

The c.5774C>T (p.P1925L) 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 5774, causing the proline (P) at amino acid position 1925 to be replaced by a leucine (L). 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	-0.20	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.075	T;T
Polyphen		0.65	P;P
Vest4		0.18
MVP		0.85
MPC		0.15
ClinPred		0.070	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.50

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: rs199884146; hg19: chr10-95072892; COSMIC: COSV63703557;