rs11768549

Variant names:

• chr7-143398060-C-T
• rs11768549
• NM_005232.5:c.1475G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005232.5(EPHA1):​c.1475G>A​(p.Arg492Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,614,006 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 33)
  • Exomes 𝑓: 0.017 (259 hom.)
• Consequence: EPHA1 NM_005232.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 20 publications found

Genes affected

EPHA1 (HGNC:3385): (EPH receptor A1) 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. This gene is expressed in some human cancer cell lines and has been implicated in carcinogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078013837).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1857/152250) while in subpopulation NFE AF = 0.0177 (1205/68012). AF 95% confidence interval is 0.0169. There are 16 homozygotes in GnomAd4. There are 908 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA1	NM_005232.5	c.1475G>A	p.Arg492Gln	missense_variant	Exon 8 of 18	ENST00000275815.4	NP_005223.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA1	ENST00000275815.4	c.1475G>A	p.Arg492Gln	missense_variant	Exon 8 of 18	1	NM_005232.5	ENSP00000275815.3
EPHA1	ENST00000488068.5	n.1627G>A		non_coding_transcript_exon_variant	Exon 7 of 16	1
EPHA1	ENST00000479459.1	n.251G>A		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1856 AN: 152132 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0124 AC: 3127 AN: 251184 AF XY: 0.0128

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00717

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0169 AC: 24692 AN: 1461756 Hom.: 259 Cov.: 33 AF XY: 0.0167 AC XY: 12115 AN XY: 727160

African (AFR) AF: 0.00269 AC: 90 AN: 33480

American (AMR) AF: 0.0118 AC: 526 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00842 AC: 220 AN: 26124

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39698

South Asian (SAS) AF: 0.00602 AC: 519 AN: 86250

European-Finnish (FIN) AF: 0.0108 AC: 576 AN: 53418

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5768

European-Non Finnish (NFE) AF: 0.0197 AC: 21886 AN: 1111926

Other (OTH) AF: 0.0130 AC: 785 AN: 60382

GnomAD4 genome AF: 0.0122 AC: 1857 AN: 152250 Hom.: 16 Cov.: 33 AF XY: 0.0122 AC XY: 908 AN XY: 74458

African (AFR) AF: 0.00397 AC: 165 AN: 41542

American (AMR) AF: 0.0175 AC: 267 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4826

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1205 AN: 68012

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0154 Hom.: 62

Bravo AF: 0.0121

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0221 AC: 85

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0121 AC: 1465

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Benign	0.62
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.39	N
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.083
Sift	Benign	0.60	T
Sift4G	Benign	0.55	T
Polyphen		0.55	P
Vest4		0.11
MPC		0.27
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.062
gMVP		0.37
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11768549; hg19: chr7-143095153; COSMIC: COSV51975355;