1-156479346-C-T

Position:

• chr1-156479346-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005920.4(MEF2D):​c.608G>A​(p.Gly203Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEF2D NM_005920.4 missense, splice_region
• Scores: Splicing: ADA: 0.9952
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

Genes affected

MEF2D (HGNC:6997): (myocyte enhancer factor 2D) This gene is a member of the myocyte-specific enhancer factor 2 (MEF2) family of transcription factors. Members of this family are involved in control of muscle and neuronal cell differentiation and development, and are regulated by class II histone deacetylases. Fusions of the encoded protein with Deleted in Azoospermia-Associated Protein 1 (DAZAP1) due to a translocation have been found in an acute lymphoblastic leukemia cell line, suggesting a role in leukemogenesis. The encoded protein may also be involved in Parkinson disease and myotonic dystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

MEF2D (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEF2D	NM_005920.4	c.608G>A	p.Gly203Glu	missense_variant, splice_region_variant	6/12	ENST00000348159.9	NP_005911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEF2D	ENST00000348159.9	c.608G>A	p.Gly203Glu	missense_variant, splice_region_variant	6/12	1	NM_005920.4	ENSP00000271555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459914 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Apr 12, 2024

The c.608G>A (p.G203E) alteration is located in exon 6 (coding exon 5) of the MEF2D gene. This alteration results from a G to A substitution at nucleotide position 608, causing the glycine (G) at amino acid position 203 to be replaced by a glutamic acid (E). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	.;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.3	.;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.035	.;D;D
Sift4G	Uncertain	0.041	D;D;D
Polyphen		0.88, 0.92	.;P;P
Vest4		0.94
MutPred		0.27		.;Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);
MVP		0.78
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.11		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: chr1-156449138;