chr1-155066988-C-T

Variant names:

• chr1-155066988-C-T
• rs114301457
• NM_005227.3:c.372C>T
• EFNA4 p.Phe124Phe

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -11 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_ModerateBP6_StrongBP7

The NM_005227.3(EFNA4):c.372C>T (p.Phe124Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00507 (AC=8,169) in the gnomAD database across 1,612,832 control chromosomes, including 45 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00524. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (41 hom.)
• Consequence: EFNA4 NM_005227.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 45.; Very high cumulative gnomAD AC = 8169 (any gene).

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>T p.Phe124Phe	synonymous	Exon 2 of 4	Prot: NP_005218.1 UniProt:
	EFNA4 NM_182689.2		c.372C>T p.Phe124Phe	synonymous	Exon 2 of 4	Prot: NP_872631.1 UniProt:
	EFNA4 NM_182690.3		c.372C>T p.Phe124Phe	synonymous	Exon 2 of 4	Prot: NP_872632.2 UniProt:

EFNA4 NM_005227.3

MANE Select

HGVSc / HGVSpc.372C>Tp.Phe124Phe

Exon rankExon 2 of 4

synonymous

Prot: NP_005218.1UniProt: P52798-1

EFNA4 NM_182689.2

HGVSc / HGVSpc.372C>Tp.Phe124Phe

Exon rankExon 2 of 4

synonymous

Prot: NP_872631.1UniProt: P52798-3

EFNA4 NM_182690.3

HGVSc / HGVSpc.372C>Tp.Phe124Phe

Exon rankExon 2 of 4

synonymous

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>T p.Phe124Phe	synonymous	Exon 2 of 4	Prot: ENSP00000357394.3 UniProt:
	EFNA4 ENST00000359751.8	TSL:1	c.372C>T p.Phe124Phe	synonymous	Exon 2 of 4	Prot: ENSP00000352789.4 UniProt:
	EFNA4-EFNA3 ENST00000505139.1	TSL:2	c.113+3052C>T	intron	Intron 1 of 4	Prot: ENSP00000426741.1 UniProt:

EFNA4 ENST00000368409.8

TSL:1MANE Select

HGVSc / HGVSpc.372C>Tp.Phe124Phe

Exon rankExon 2 of 4

synonymous

Prot: ENSP00000357394.3UniProt: P52798-1

EFNA4 ENST00000359751.8

TSL:1

HGVSc / HGVSpc.372C>Tp.Phe124Phe

Exon rankExon 2 of 4

synonymous

Prot: ENSP00000352789.4UniProt: P52798-2

EFNA4-EFNA3 ENST00000505139.1

TSL:2

HGVSc / HGVSpc.113+3052C>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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00450	AC:685	Hom:4	AN:152202	Cov:32
GnomAD2 exomes	AF: 0.00464	AC:1160	Hom:	AN:249734	Cov:
GnomAD4 exome	AF: 0.00512	AC:7484	Hom:41	AN:1460512	Cov:32
GnomAD4 genome	AF: 0.00450	AC:685	Hom:4	AN:152320	Cov:32
TOPMed (Bravo)	AF: 0.00314	AC:831	Hom:2	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00422	AC:317	Hom:0	AN:75092	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00342	AC:8	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000295	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.00667	AC:2	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00331	AC:43	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00318	AC:11	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00110	AC:2	Hom:	AN:1882	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00	AC:0	Hom:0	AN:122478	Cov:
Turkish Variome	AF: 0.00554	AC:37	Hom:2	AN:6682	Cov:
UK10K	AF: 0.00502	AC:38	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000335	AC:3	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00811 *	12	1480	0.00695 *	50	7190
BipEx(Bipolar disorder (including schizoaffective))	0.00602	171	28418	0.00624	180	28844
Epi25(Epilepsy)	0.00489	205	41958	0.00428	286	66884
SCHEMA(Schizophrenia)	0.00523	593	113358	0.00487	929	190700

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.2
DANN	Benign	0.82
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
Mutation Taster	N/A	99/1	polymorphism
PhyloP100	Benign	1.1

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
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: rs114301457;

hg19: chr1-155039464;

COSMIC: COSV99664919;

COSMIC: COSV99664919;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar