rs2278107

Variant names:

• chr6-93410921-T-C
• rs2278107
• NM_004440.4:c.412A>G
• EPHA7 p.Ile138Val

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 26 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004440.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA7	NM_004440.4	MANE Select	c.412A>G	p.Ile138Val	missense	Exon 3 of 17	NP_004431.1	Q15375-1
	EPHA7	NM_001376465.1		c.412A>G	p.Ile138Val	missense	Exon 3 of 17	NP_001363394.1	Q15375-4
	EPHA7	NM_001288629.2		c.412A>G	p.Ile138Val	missense	Exon 3 of 17	NP_001275558.1	Q15375-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA7	ENST00000369303.9	TSL:1 MANE Select	c.412A>G	p.Ile138Val	missense	Exon 3 of 17	ENSP00000358309.4	Q15375-1
	EPHA7	ENST00000369297.1	TSL:1	c.412A>G	p.Ile138Val	missense	Exon 3 of 3	ENSP00000358303.1	Q15375-3
	EPHA7	ENST00000922908.1		c.412A>G	p.Ile138Val	missense	Exon 3 of 17	ENSP00000592967.1

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

GnomAD2 exomes AF: 0.0527 AC: 13231 AN: 251136 AF XY: 0.0508

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 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

African (AFR) AF: 0.00580 AC: 194 AN: 33442

American (AMR) AF: 0.0913 AC: 4080 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 405 AN: 26112

East Asian (EAS) AF: 0.153 AC: 6075 AN: 39700

South Asian (SAS) AF: 0.0581 AC: 5013 AN: 86252

European-Finnish (FIN) AF: 0.0363 AC: 1937 AN: 53410

Middle Eastern (MID) AF: 0.0279 AC: 161 AN: 5766

European-Non Finnish (NFE) AF: 0.0331 AC: 36805 AN: 1111932

Other (OTH) AF: 0.0440 AC: 2659 AN: 60384

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

African (AFR) AF: 0.00751 AC: 312 AN: 41570

American (AMR) AF: 0.0704 AC: 1077 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.166 AC: 860 AN: 5168

South Asian (SAS) AF: 0.0611 AC: 295 AN: 4830

European-Finnish (FIN) AF: 0.0364 AC: 387 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0335 AC: 2281 AN: 68018

Other (OTH) AF: 0.0502 AC: 106 AN: 2112

Alfa AF: 0.0370 Hom.: 736

Bravo AF: 0.0363

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 v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.086
Sift	Benign	0.12	T
Sift4G	Benign	0.47	T
Varity_R		0.18
gMVP		0.36
Mutation Taster		=97/3	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2278107;

hg19: chr6-94120639;

COSMIC: COSV65168696;