rs2278107

Positions:

• chr6-93410921-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004440.4(EPHA7):​c.412A>G​(p.Ile138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,988 control chromosomes in the GnomAD database, including 1,801 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (170 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1631 hom.)
• Consequence: EPHA7 NM_004440.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07

Genes affected

EPHA7 (HGNC:3390): (EPH receptor A7) 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. Increased expression of this gene is associated with multiple forms of carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

EPHA7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017443001).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA7	NM_004440.4	c.412A>G	p.Ile138Val	missense_variant	3/17	ENST00000369303.9	NP_004431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA7	ENST00000369303.9	c.412A>G	p.Ile138Val	missense_variant	3/17	1	NM_004440.4	ENSP00000358309.4

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5385 AN: 152174 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.00753

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0606

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0474

GnomAD3 exomes AF: 0.0527 AC: 13231 AN: 251136 Hom.: 616 AF XY: 0.0508 AC XY: 6895 AN XY: 135740

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.0946

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.0570

Gnomad FIN exome AF: 0.0347

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0473

GnomAD4 exome AF: 0.0392 AC: 57329 AN: 1461696 Hom.: 1631 Cov.: 33 AF XY: 0.0396 AC XY: 28809 AN XY: 727162

Gnomad4 AFR exome AF: 0.00580

Gnomad4 AMR exome AF: 0.0913

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.0581

Gnomad4 FIN exome AF: 0.0363

Gnomad4 NFE exome AF: 0.0331

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0354 AC: 5387 AN: 152292 Hom.: 170 Cov.: 32 AF XY: 0.0370 AC XY: 2759 AN XY: 74470

Gnomad4 AFR AF: 0.00751

Gnomad4 AMR AF: 0.0704

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.0611

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0335

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0371 Hom.: 417

Bravo AF: 0.0363

TwinsUK AF: 0.0321 AC: 119

ALSPAC AF: 0.0317 AC: 122

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0299 AC: 257

ExAC AF: 0.0498 AC: 6040

Asia WGS AF: 0.0960 AC: 331 AN: 3478

EpiCase AF: 0.0331

EpiControl AF: 0.0315

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.086
Sift	Benign	0.12	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.010	B;B
Vest4		0.10
MPC		0.32
ClinPred		0.018	T
GERP RS		4.3
Varity_R		0.18
gMVP		0.36

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: rs2278107; hg19: chr6-94120639; COSMIC: COSV65168696;