1-156482624-C-T

Position:

• chr1-156482624-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005920.4(MEF2D):​c.71G>A​(p.Arg24Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEF2D NM_005920.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEF2D	NM_005920.4	c.71G>A	p.Arg24Gln	missense_variant	3/12	ENST00000348159.9	NP_005911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEF2D	ENST00000348159.9	c.71G>A	p.Arg24Gln	missense_variant	3/12	1	NM_005920.4	ENSP00000271555.5
MEF2D	ENST00000360595.7	c.71G>A	p.Arg24Gln	missense_variant	3/11	1		ENSP00000353803.3
MEF2D	ENST00000464356.6	c.71G>A	p.Arg24Gln	missense_variant	2/10	5		ENSP00000476788.1
MEF2D	ENST00000475587.2	n.71G>A		non_coding_transcript_exon_variant	3/9	5		ENSP00000477413.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	.;D;.;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.4	.;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.91
MutPred		0.91		Loss of MoRF binding (P = 0.0314);Loss of MoRF binding (P = 0.0314);Loss of MoRF binding (P = 0.0314);Loss of MoRF binding (P = 0.0314);
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.83
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1672096301; hg19: chr1-156452416; COSMIC: COSV100559846; COSMIC: COSV100559846;