12-80717206-G-A

Position:

• chr12-80717206-G-A

Variant summary

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

The NM_005593.3(MYF5):​c.143G>A​(p.Gly48Asp) variant causes a missense change. 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: MYF5 NM_005593.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYF5	NM_005593.3	c.143G>A	p.Gly48Asp	missense_variant	1/3	ENST00000228644.4	NP_005584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYF5	ENST00000228644.4	c.143G>A	p.Gly48Asp	missense_variant	1/3	1	NM_005593.3	ENSP00000228644.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Feb 27, 2024

The c.143G>A (p.G48D) alteration is located in exon 1 (coding exon 1) of the MYF5 gene. This alteration results from a G to A substitution at nucleotide position 143, causing the glycine (G) at amino acid position 48 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0046	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.27
Sift	Benign	0.14	T
Sift4G	Benign	0.37	T
Polyphen		0.25	B
Vest4		0.54
MutPred		0.51		Gain of methylation at K43 (P = 0.0629);
MVP		0.84
MPC		0.49
ClinPred		0.67	D
GERP RS		6.2
Varity_R		0.11
gMVP		0.36

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: rs1868622681; hg19: chr12-81110985;