rs4745

Positions:

• chr1-155133751-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000368407.8(EFNA1):​c.476A>T​(p.Asp159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,502 control chromosomes in the GnomAD database, including 200,789 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D159E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (14138 hom., cov: 31)
  • Exomes 𝑓: 0.50 (186651 hom.)
• Consequence: EFNA1 ENST00000368407.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.349

Genes affected

EFNA1 (HGNC:3221): (ephrin A1) 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 which binds to the EPHA2, EPHA4, EPHA5, EPHA6, and EPHA7 receptors. Two transcript variants that encode different isoforms were identified through sequence analysis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.9061713E-5).
• BP6: Variant 1-155133751-A-T is Benign according to our data. Variant chr1-155133751-A-T is described in ClinVar as [Benign]. Clinvar id is 1268289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFNA1	NM_004428.3	c.476A>T	p.Asp159Val	missense_variant	4/5	ENST00000368407.8	NP_004419.2
EFNA1	NM_182685.2	c.410A>T	p.Asp137Val	missense_variant	3/4		NP_872626.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFNA1	ENST00000368407.8	c.476A>T	p.Asp159Val	missense_variant	4/5	1	NM_004428.3	ENSP00000357392	P1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60864 AN: 151790 Hom.: 14132 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.494

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.441

GnomAD3 exomes AF: 0.447 AC: 112467 AN: 251430 Hom.: 27442 AF XY: 0.463 AC XY: 62934 AN XY: 135894

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.471

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.533

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.496 AC: 725303 AN: 1461594 Hom.: 186651 Cov.: 62 AF XY: 0.500 AC XY: 363399 AN XY: 727130

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.584

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.510

Gnomad4 NFE exome AF: 0.525

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.401 AC: 60881 AN: 151908 Hom.: 14138 Cov.: 31 AF XY: 0.403 AC XY: 29913 AN XY: 74222

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.588

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.527

Gnomad4 OTH AF: 0.443

Alfa AF: 0.506 Hom.: 15334

Bravo AF: 0.377

TwinsUK AF: 0.535 AC: 1982

ALSPAC AF: 0.512 AC: 1972

ESP6500AA AF: 0.174 AC: 766

ESP6500EA AF: 0.529 AC: 4547

ExAC AF: 0.448 AC: 54439

Asia WGS AF: 0.326 AC: 1133 AN: 3478

EpiCase AF: 0.549

EpiControl AF: 0.555

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2019	This variant is associated with the following publications: (PMID: 29748316, 29083408) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.6
DANN	Benign	0.93
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.000039	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.0065	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.67	N;N
REVEL	Benign	0.24
Sift	Benign	0.63	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;B
Vest4		0.053
MPC		0.27
ClinPred		0.0087	T
GERP RS		-0.26
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.11
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4745; hg19: chr1-155106227; COSMIC: COSV57596245; COSMIC: COSV57596245;