chr2-221426131-C-G

Position:

• chr2-221426131-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_004438.5(EPHA4):​c.2858G>C​(p.Arg953Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R953K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EPHA4 NM_004438.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA4	NM_004438.5	c.2858G>C	p.Arg953Thr	missense_variant	17/18	ENST00000281821.7	NP_004429.1
EPHA4	NM_001304536.2	c.2858G>C	p.Arg953Thr	missense_variant	18/19		NP_001291465.1
EPHA4	NM_001304537.2	c.2705G>C	p.Arg902Thr	missense_variant	16/17		NP_001291466.1
EPHA4	NM_001363748.2	c.*37G>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.2858G>C	p.Arg953Thr	missense_variant	17/18	1	NM_004438.5	ENSP00000281821	P1
EPHA4	ENST00000409854.5	c.*37G>C		3_prime_UTR_variant	17/17	1		ENSP00000386276
EPHA4	ENST00000409938.5	c.2858G>C	p.Arg953Thr	missense_variant	18/18	2		ENSP00000386829	P1
EPHA4	ENST00000424339.1	c.*162G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	2		ENSP00000408145

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251422 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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

Nov 03, 2022

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 953 of the EPHA4 protein (p.Arg953Thr). This variant is present in population databases (rs35341687, gnomAD 0.009%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1522358). This variant has not been reported in the literature in individuals affected with EPHA4-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.92	P;P
Vest4		0.72
MutPred		0.47		Loss of MoRF binding (P = 0.0264);Loss of MoRF binding (P = 0.0264);
MVP		0.76
MPC		1.9
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.63
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35341687; hg19: chr2-222290851;