chr1-155066988-C-G

Variant names:

• chr1-155066988-C-G
• rs114301457
• NM_005227.3:c.372C>G
• EFNA4 p.Phe124Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

The NM_005227.3(EFNA4):c.372C>G (p.Phe124Leu) 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 0.00000205 (AC=3) in the gnomAD database across 1,460,516 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F124= (synonymous): Benign/Likely_benign (ClinVar VariationId 710307, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EFNA4 NM_005227.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 10 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 1 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 = 0.000000 — very rare (O3 supporting [+1])

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.372C>G p.Phe124Leu	missense	Exon 2 of 4	Prot: NP_005218.1 UniProt:
	EFNA4 NM_182689.2		c.372C>G p.Phe124Leu	missense	Exon 2 of 4	Prot: NP_872631.1 UniProt:
	EFNA4 NM_182690.3		c.372C>G p.Phe124Leu	missense	Exon 2 of 4	Prot: NP_872632.2 UniProt:

EFNA4 NM_005227.3

MANE Select

HGVSc / HGVSpc.372C>Gp.Phe124Leu

Exon rankExon 2 of 4

missense

Prot: NP_005218.1UniProt: P52798-1

EFNA4 NM_182689.2

HGVSc / HGVSpc.372C>Gp.Phe124Leu

Exon rankExon 2 of 4

missense

Prot: NP_872631.1UniProt: P52798-3

EFNA4 NM_182690.3

HGVSc / HGVSpc.372C>Gp.Phe124Leu

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.372C>G p.Phe124Leu	missense	Exon 2 of 4	Prot: ENSP00000357394.3 UniProt:
	EFNA4 ENST00000359751.8	TSL:1	c.372C>G p.Phe124Leu	missense	Exon 2 of 4	Prot: ENSP00000352789.4 UniProt:
	EFNA4-EFNA3 ENST00000505139.1	TSL:2	c.113+3052C>G	intron	Intron 1 of 4	Prot: ENSP00000426741.1 UniProt:

EFNA4 ENST00000368409.8

TSL:1MANE Select

HGVSc / HGVSpc.372C>Gp.Phe124Leu

Exon rankExon 2 of 4

missense

Prot: ENSP00000357394.3UniProt: P52798-1

EFNA4 ENST00000359751.8

TSL:1

HGVSc / HGVSpc.372C>Gp.Phe124Leu

Exon rankExon 2 of 4

missense

Prot: ENSP00000352789.4UniProt: P52798-2

EFNA4-EFNA3 ENST00000505139.1

TSL:2

HGVSc / HGVSpc.113+3052C>G

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000801	AC:2	Hom:	AN:249734	Cov:
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1460516	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000178	AC:1	Hom:0	AN:5138	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.85	D
FuncVEP CTI	Pathogenic	0.89
GPN-Star LLR	N/A	-8.8
GPN-Star score	N/A	8.8
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.29	T
Mutation Taster	N/A	89/11	polymorphism
MutationAssessor	Pathogenic	3.5	H
PhyloP100	Benign	1.1
popEVE	Benign	-3.8
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Varity_R	N/A	0.82
VESM-3B	Benign	-10

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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: rs114301457;

hg19: chr1-155039464;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar