1-155066794-C-G

Variant names:

• chr1-155066794-C-G
• rs148289726
• NM_005227.3:c.178C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_005227.3(EFNA4):​c.178C>G​(p.His60Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,612,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H60R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: EFNA4 NM_005227.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 9 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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• BS2: High AC in GnomAdExome4 at 6 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.178C>G	p.His60Asp	missense	Exon 2 of 4	NP_005218.1
	EFNA4	NM_182689.2		c.178C>G	p.His60Asp	missense	Exon 2 of 4	NP_872631.1
	EFNA4	NM_182690.3		c.178C>G	p.His60Asp	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.178C>G	p.His60Asp	missense	Exon 2 of 4	ENSP00000357394.3
	EFNA4	ENST00000359751.8	TSL:1	c.178C>G	p.His60Asp	missense	Exon 2 of 4	ENSP00000352789.4
	EFNA4-EFNA3	ENST00000505139.1	TSL:2	c.113+2858C>G		intron	N/A	ENSP00000426741.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249144 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460372 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726592

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.0000226 AC: 1 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.0000938 AC: 5 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111550

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.7
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.67		Gain of disorder (P = 0.1498)
MVP		0.99
MPC		1.7
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.70
Mutation Taster		=38/62	disease causing

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: rs148289726; hg19: chr1-155039270;