1-156479346-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

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

9
7
3
Splicing: ADA: 0.9952
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.23
Variant links:
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]

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ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
MEF2DNM_005920.4 linkc.608G>A p.Gly203Glu missense_variant, splice_region_variant Exon 6 of 12 ENST00000348159.9 NP_005911.1 Q14814-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEF2DENST00000348159.9 linkc.608G>A p.Gly203Glu missense_variant, splice_region_variant Exon 6 of 12 1 NM_005920.4 ENSP00000271555.5 Q14814-1

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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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; API