2-221426039-C-G

Position:

• chr2-221426039-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004438.5(EPHA4):​c.2950G>C​(p.Val984Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: EPHA4 NM_004438.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

EPHA4 (HGNC:3388): (EPH receptor A4) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EPHA4. . Gene score misZ 2.8852 (greater than the threshold 3.09). Trascript score misZ 4.018 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA4	NM_004438.5	c.2950G>C	p.Val984Leu	missense_variant	17/18	ENST00000281821.7	NP_004429.1
EPHA4	NM_001304536.2	c.2950G>C	p.Val984Leu	missense_variant	18/19		NP_001291465.1
EPHA4	NM_001304537.2	c.2797G>C	p.Val933Leu	missense_variant	16/17		NP_001291466.1
EPHA4	NM_001363748.2	c.*129G>C		3_prime_UTR_variant	17/18		NP_001350677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA4	ENST00000281821.7	c.2950G>C	p.Val984Leu	missense_variant	17/18	1	NM_004438.5	ENSP00000281821	P1
EPHA4	ENST00000409854.5	c.*129G>C		3_prime_UTR_variant	17/17	1		ENSP00000386276
EPHA4	ENST00000409938.5	c.2950G>C	p.Val984Leu	missense_variant	18/18	2		ENSP00000386829	P1
EPHA4	ENST00000424339.1	c.*254G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	2		ENSP00000408145

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with EPHA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 984 of the EPHA4 protein (p.Val984Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	-0.0015	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.49	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.057	T;T
Polyphen		0.99	D;D
Vest4		0.58
MutPred		0.23		Loss of methylation at R982 (P = 0.1508);Loss of methylation at R982 (P = 0.1508);
MVP		0.70
MPC		1.3
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.28
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-222290759;