NM_005227.3:c.229_231delATGinsGTC

Variant names:

• chr1-155066845-ATG-GTC
• NM_005227.3:c.229_231delATGinsGTC
• EFNA4 p.Met77Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_005227.3(EFNA4):c.229_231delATGinsGTC (p.Met77Val) variant causes a missense change. The gene EFNA4 is a known oncogene (CancerMine: 4 oncogene citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.64). 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.M77V: Uncertain_significance (ClinVar VariationId 2519275, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFNA4 NM_005227.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.63
• 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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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.229_231delATGinsGTC p.Met77Val	missense	N/A	Prot: NP_005218.1 UniProt:
	EFNA4 NM_001406810.1		c.1_3delATGinsGTC p.Met1?	start_lost	N/A	Prot: NP_001393739.1
	EFNA4 NM_182689.2		c.229_231delATGinsGTC p.Met77Val	missense	N/A	Prot: NP_872631.1 UniProt:

EFNA4 NM_005227.3

MANE Select

HGVSc / HGVSpc.229_231delATGinsGTCp.Met77Val

Exon rankN/A

missense

Prot: NP_005218.1UniProt: P52798-1

EFNA4 NM_001406810.1

HGVSc / HGVSpc.1_3delATGinsGTCp.Met1?

Exon rankN/A

start_lost

Prot: NP_001393739.1

EFNA4 NM_182689.2

HGVSc / HGVSpc.229_231delATGinsGTCp.Met77Val

Exon rankN/A

missense

Prot: NP_872631.1UniProt: P52798-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	EFNA4 ENST00000368409.8	TSL:1MANE Select	c.229_231delATGinsGTC p.Met77Val	missense	N/A	Prot: ENSP00000357394.3 UniProt:
	EFNA4 ENST00000359751.8	TSL:1	c.229_231delATGinsGTC p.Met77Val	missense	N/A	Prot: ENSP00000352789.4 UniProt:
	EFNA4-EFNA3 ENST00000505139.1	TSL:2	c.113+2909_113+2911delATGinsGTC	intron	Intron 1 of 4	Prot: ENSP00000426741.1 UniProt:

EFNA4 ENST00000368409.8

TSL:1MANE Select

HGVSc / HGVSpc.229_231delATGinsGTCp.Met77Val

Exon rankN/A

missense

Prot: ENSP00000357394.3UniProt: P52798-1

EFNA4 ENST00000359751.8

TSL:1

HGVSc / HGVSpc.229_231delATGinsGTCp.Met77Val

Exon rankN/A

missense

Prot: ENSP00000352789.4UniProt: P52798-2

EFNA4-EFNA3 ENST00000505139.1

TSL:2

HGVSc / HGVSpc.113+2909_113+2911delATGinsGTC

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr1-155039321;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar