chr2-221436503-C-T

Position:

• chr2-221436503-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004438.5(EPHA4):​c.2242G>A​(p.Ala748Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPHA4 NM_004438.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 2-221436503-C-T is Pathogenic according to our data. Variant chr2-221436503-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431727.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA4	NM_004438.5	c.2242G>A	p.Ala748Thr	missense_variant	13/18	ENST00000281821.7	NP_004429.1
EPHA4	NM_001304536.2	c.2242G>A	p.Ala748Thr	missense_variant	14/19		NP_001291465.1
EPHA4	NM_001363748.2	c.2242G>A	p.Ala748Thr	missense_variant	13/18		NP_001350677.1
EPHA4	NM_001304537.2	c.2089G>A	p.Ala697Thr	missense_variant	12/17		NP_001291466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA4	ENST00000281821.7	c.2242G>A	p.Ala748Thr	missense_variant	13/18	1	NM_004438.5	ENSP00000281821.2
EPHA4	ENST00000409854.5	c.2242G>A	p.Ala748Thr	missense_variant	13/17	1		ENSP00000386276.1
EPHA4	ENST00000409938.5	c.2242G>A	p.Ala748Thr	missense_variant	14/18	2		ENSP00000386829.1
EPHA4	ENST00000495693.1	n.542G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

atypical cerebral palsy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

TIDEX, University of British Columbia

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.92
MutPred		0.90		Gain of phosphorylation at A748 (P = 0.0899);Gain of phosphorylation at A748 (P = 0.0899);Gain of phosphorylation at A748 (P = 0.0899);
MVP		0.85
MPC		1.5
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.72
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs1553568456; hg19: chr2-222301223;