2-221426109-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004438.5(EPHA4):c.2880G>A(p.Thr960=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0942 in 1,613,664 control chromosomes in the GnomAD database, including 8,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.090 (736 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7293 hom.)
• Consequence: EPHA4 NM_004438.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.45

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-221426109-C-T is Benign according to our data. Variant chr2-221426109-C-T is described in ClinVar as [Benign]. Clinvar id is 1167926.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA4	NM_004438.5	c.2880G>A	p.Thr960=	synonymous_variant	17/18	ENST00000281821.7
EPHA4	NM_001304536.2	c.2880G>A	p.Thr960=	synonymous_variant	18/19
EPHA4	NM_001304537.2	c.2727G>A	p.Thr909=	synonymous_variant	16/17
EPHA4	NM_001363748.2	c.*59G>A		3_prime_UTR_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA4	ENST00000281821.7	c.2880G>A	p.Thr960=	synonymous_variant	17/18	1	NM_004438.5	P1
EPHA4	ENST00000409854.5	c.*59G>A		3_prime_UTR_variant	17/17	1
EPHA4	ENST00000409938.5	c.2880G>A	p.Thr960=	synonymous_variant	18/18	2		P1
EPHA4	ENST00000424339.1	c.*184G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0904 AC: 13737 AN: 151914 Hom.: 736 Cov.: 32

Gnomad AFR AF: 0.0818

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0835

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0967

Gnomad OTH AF: 0.101

GnomAD3 exomes AF: 0.0930 AC: 23377 AN: 251456 Hom.: 1377 AF XY: 0.0974 AC XY: 13236 AN XY: 135898

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.0521

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.0821

Gnomad NFE exome AF: 0.0987

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0946 AC: 138199 AN: 1461632 Hom.: 7293 Cov.: 32 AF XY: 0.0968 AC XY: 70380 AN XY: 727140

Gnomad4 AFR exome AF: 0.0871

Gnomad4 AMR exome AF: 0.0543

Gnomad4 ASJ exome AF: 0.213

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.0830

Gnomad4 NFE exome AF: 0.0931

Gnomad4 OTH exome AF: 0.0980

GnomAD4 genome AF: 0.0903 AC: 13736 AN: 152032 Hom.: 736 Cov.: 32 AF XY: 0.0920 AC XY: 6841 AN XY: 74330

Gnomad4 AFR AF: 0.0815

Gnomad4 AMR AF: 0.0811

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.0835

Gnomad4 NFE AF: 0.0967

Gnomad4 OTH AF: 0.100

Alfa AF: 0.105 Hom.: 488

Bravo AF: 0.0867

Asia WGS AF: 0.0540 AC: 189 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	3.1
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35860178; hg19: chr2-222290829; COSMIC: COSV56027042; COSMIC: COSV56027042;