10-93310601-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013451.4(MYOF):c.5932G>A(p.Ala1978Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOF NM_013451.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOF	NM_013451.4	c.5932G>A	p.Ala1978Thr	missense_variant	52/54	ENST00000359263.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOF	ENST00000359263.9	c.5932G>A	p.Ala1978Thr	missense_variant	52/54	1	NM_013451.4	P1
MYOF	ENST00000358334.9	c.5893G>A	p.Ala1965Thr	missense_variant	51/53	1
MYOF	ENST00000463743.5	c.*491G>A		3_prime_UTR_variant, NMD_transcript_variant	32/34	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 03, 2024

The c.5932G>A (p.A1978T) alteration is located in exon 52 (coding exon 52) of the MYOF gene. This alteration results from a G to A substitution at nucleotide position 5932, causing the alanine (A) at amino acid position 1978 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.51	D
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.25	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.43	B;P
Vest4		0.67
MutPred		0.25		.;Gain of phosphorylation at A1978 (P = 0.0065);
MVP		0.94
MPC		0.23
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.15
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-95070358;