chr1-16129440-G-C

Variant names:

• chr1-16129440-G-C
• rs137853200
• NM_004431.5:c.2819C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_004431.5(EPHA2):​c.2819C>G​(p.Thr940Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. T940I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• 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 Gene-Disease associations (from GenCC):

• cataract 6 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• early-onset non-syndromic cataract

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-16129440-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13259.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19970071).

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.2819C>G	p.Thr940Ser	missense	Exon 16 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.2657C>G	p.Thr886Ser	missense	Exon 15 of 16	NP_001316019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.2819C>G	p.Thr940Ser	missense	Exon 16 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.2834C>G	p.Thr945Ser	missense	Exon 16 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.2798C>G	p.Thr933Ser	missense	Exon 16 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.31
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.11
Sift	Benign	0.42	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.68		Gain of methylation at K935 (P = 0.1144)
MVP		0.39
MPC		0.56
ClinPred		0.37	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.51
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137853200; hg19: chr1-16455935;