12-80717114-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005593.3(MYF5):c.51C>G(p.Asp17Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYF5 NM_005593.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.654

Genes affected

MYF5 (HGNC:7565): (myogenic factor 5) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to contribute to E-box binding activity. Predicted to be involved in several processes, including muscle cell fate commitment; positive regulation of cell differentiation; and skeletal muscle cell differentiation. Predicted to act upstream of or within several processes, including animal organ development; regulation of cell-matrix adhesion; and somitogenesis. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22811723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYF5	NM_005593.3	c.51C>G	p.Asp17Glu	missense_variant	1/3	ENST00000228644.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYF5	ENST00000228644.4	c.51C>G	p.Asp17Glu	missense_variant	1/3	1	NM_005593.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ophthalmoplegia, external, with rib and vertebral anomalies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 14, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.50
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.020	D
Sift4G	Benign	0.12	T
Polyphen		0.015	B
Vest4		0.11
MutPred		0.64		Gain of disorder (P = 0.0902);
MVP		0.75
MPC		0.17
ClinPred		0.43	T
GERP RS		-2.0
Varity_R		0.14
gMVP		0.39

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: rs1229470428; hg19: chr12-81110893;