1-16155856-C-T

Variant names:

• chr1-16155856-C-T
• rs1557520529
• NM_004431.5:c.77G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004431.5(EPHA2):​c.77G>A​(p.Gly26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000307 in 1,302,532 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G26V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.397
• Publications: 0 publications found

Genes affected

EPHA2 (HGNC:3386): (EPH receptor A2) 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 encodes a protein that binds ephrin-A ligands. Mutations in this gene are the cause of certain genetically-related cataract disorders.[provided by RefSeq, May 2010]

EPHA2-AS1 (HGNC:40216): (EPHA2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004431.5. 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
	EPHA2	NM_004431.5	MANE Select	c.77G>A	p.Gly26Asp	missense	Exon 1 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.-18G>A		5_prime_UTR	Exon 1 of 16	NP_001316019.1
	EPHA2-AS1	NR_187272.1		n.541+101C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.77G>A	p.Gly26Asp	missense	Exon 1 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.77G>A	p.Gly26Asp	missense	Exon 1 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.77G>A	p.Gly26Asp	missense	Exon 1 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000307 AC: 4 AN: 1302532 Hom.: 0 Cov.: 30 AF XY: 0.00000312 AC XY: 2 AN XY: 640286

African (AFR) AF: 0.00 AC: 0 AN: 26172

American (AMR) AF: 0.00 AC: 0 AN: 23354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22268

East Asian (EAS) AF: 0.00 AC: 0 AN: 28634

South Asian (SAS) AF: 0.00 AC: 0 AN: 69216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4864

European-Non Finnish (NFE) AF: 0.00000384 AC: 4 AN: 1041522

Other (OTH) AF: 0.00 AC: 0 AN: 54018

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.063
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.40
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.47		Loss of sheet (P = 0.0181)
MVP		0.94
MPC		0.84
ClinPred		0.56	D
GERP RS		4.5
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.36
gMVP		0.61
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs1557520529; hg19: chr1-16482351;