NM_005227.3:c.280T>G

Variant names:

• chr1-155066896-T-G
• rs1286500741
• NM_005227.3:c.280T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005227.3(EFNA4):​c.280T>G​(p.Tyr94Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: EFNA4 NM_005227.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

Genes affected

EFNA4 (HGNC:3224): (ephrin A4) This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNA class ephrin that has been implicated in proliferation and metastasis of several types of cancers. [provided by RefSeq, May 2022]

EFNA4-EFNA3 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32339603).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005227.3. 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
	EFNA4	NM_005227.3	MANE Select	c.280T>G	p.Tyr94Asp	missense	Exon 2 of 4	NP_005218.1
	EFNA4	NM_182689.2		c.280T>G	p.Tyr94Asp	missense	Exon 2 of 4	NP_872631.1
	EFNA4	NM_182690.3		c.280T>G	p.Tyr94Asp	missense	Exon 2 of 4	NP_872632.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNA4	ENST00000368409.8	TSL:1 MANE Select	c.280T>G	p.Tyr94Asp	missense	Exon 2 of 4	ENSP00000357394.3
	EFNA4	ENST00000359751.8	TSL:1	c.280T>G	p.Tyr94Asp	missense	Exon 2 of 4	ENSP00000352789.4
	EFNA4-EFNA3	ENST00000505139.1	TSL:2	c.113+2960T>G		intron	N/A	ENSP00000426741.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251266 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.022	D
Polyphen		0.86	P
Vest4		0.34
MutPred		0.51		Gain of ubiquitination at K95 (P = 0.0581)
MVP		0.95
MPC		0.90
ClinPred		0.65	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.49
Mutation Taster		=92/8	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: rs1286500741; hg19: chr1-155039372;