EFNA4 p.Pro91Leu

Variant names:

• chr1-155066888-C-T
• rs1407731922
• NM_005227.3:c.272C>T
• EFNA4 p.Pro91Leu

Your query was ambiguous. Multiple possible variants found:

• chr1-155066888-C-T
• chr1-155066888-CC-TA
• chr1-155066888-CC-TG
• chr1-155066888-CC-TT
• chr1-155066887-CCC-TTA
• chr1-155066887-CCC-TTG

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingB3_Supporting

The NM_005227.3(EFNA4):c.272C>T (p.Pro91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene EFNA4 is a known oncogene (CancerMine: 4 oncogene citations). The variant allele was found at a cumulative frequency of 0.00000372 (AC=6) in the gnomAD database across 1,614,034 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EFNA4 NM_005227.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• 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 Gene-Disease associations (from GenCC):

• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

EFNA4-EFNA3 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000005 — very rare (O3 supporting [+1])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005227.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	EFNA4 NM_005227.3	MANE Select	c.272C>T p.Pro91Leu	missense	Exon 2 of 4	Prot: NP_005218.1 UniProt:
	EFNA4 NM_182689.2		c.272C>T p.Pro91Leu	missense	Exon 2 of 4	Prot: NP_872631.1 UniProt:
	EFNA4 NM_182690.3		c.272C>T p.Pro91Leu	missense	Exon 2 of 4	Prot: NP_872632.2 UniProt:

EFNA4 NM_005227.3

MANE Select

HGVSc / HGVSpc.272C>Tp.Pro91Leu

Exon rankExon 2 of 4

missense

Prot: NP_005218.1UniProt: P52798-1

EFNA4 NM_182689.2

HGVSc / HGVSpc.272C>Tp.Pro91Leu

Exon rankExon 2 of 4

missense

Prot: NP_872631.1UniProt: P52798-3

EFNA4 NM_182690.3

HGVSc / HGVSpc.272C>Tp.Pro91Leu

Exon rankExon 2 of 4

missense

Prot: NP_872632.2UniProt: P52798-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	EFNA4 ENST00000368409.8	TSL:1MANE Select	c.272C>T p.Pro91Leu	missense	Exon 2 of 4	Prot: ENSP00000357394.3 UniProt:
	EFNA4 ENST00000359751.8	TSL:1	c.272C>T p.Pro91Leu	missense	Exon 2 of 4	Prot: ENSP00000352789.4 UniProt:
	EFNA4-EFNA3 ENST00000505139.1	TSL:2	c.113+2952C>T	intron	Intron 1 of 4	Prot: ENSP00000426741.1 UniProt:

EFNA4 ENST00000368409.8

TSL:1MANE Select

HGVSc / HGVSpc.272C>Tp.Pro91Leu

Exon rankExon 2 of 4

missense

Prot: ENSP00000357394.3UniProt: P52798-1

EFNA4 ENST00000359751.8

TSL:1

HGVSc / HGVSpc.272C>Tp.Pro91Leu

Exon rankExon 2 of 4

missense

Prot: ENSP00000352789.4UniProt: P52798-2

EFNA4-EFNA3 ENST00000505139.1

TSL:2

HGVSc / HGVSpc.113+2952C>T

Exon rankIntron 1 of 4

intron

Prot: ENSP00000426741.1UniProt: K9J7H7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152254	Cov:32
GnomAD4 exome	AF: 0.00000274	AC:4	Hom:0	AN:1461780	Cov:32
GnomAD4 genome Warning	AF: 0.0000131	AC:2	Hom:0	AN:152254	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
SCHEMA(Schizophrenia)	0.0000129	1	77664	0.00	0	139302

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.17	N
FuncVEP CTI	Benign	0.097
GPN-Star LLR	N/A	-4.8
GPN-Star score	N/A	4.8
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.015	D
Mutation Taster	N/A	94/6	polymorphism
MutationAssessor	Uncertain	2.4	M
PhyloP100	Benign	1.4
popEVE	Benign	-3.5
PROVEAN	Benign	-1.8	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.095	T
Varity_R	N/A	0.11
VESM-3B	Benign	-6.8

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1407731922;

hg19: chr1-155039364;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar