1-155068855-T-A

Position:

• chr1-155068855-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005227.3(EFNA4):​c.472T>A​(p.Ser158Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EFNA4 NM_005227.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.700

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1003682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFNA4	NM_005227.3	c.472T>A	p.Ser158Thr	missense_variant, splice_region_variant	4/4	ENST00000368409.8	NP_005218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFNA4	ENST00000368409.8	c.472T>A	p.Ser158Thr	missense_variant, splice_region_variant	4/4	1	NM_005227.3	ENSP00000357394.3
EFNA4-EFNA3	ENST00000505139.1	c.113+4919T>A		intron_variant		2		ENSP00000426741.1
EFNA4	ENST00000359751.8	c.470-144T>A		intron_variant		1		ENSP00000352789.4
EFNA4	ENST00000427683.2	c.470-164T>A		intron_variant		2		ENSP00000414378.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 08, 2022

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 158 of the EFNA4 protein (p.Ser158Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EFNA4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.34	N
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.21
Sift	Benign	0.41	T
Sift4G	Benign	0.52	T
Polyphen		0.14	B
Vest4		0.26
MutPred		0.29		Loss of ubiquitination at K154 (P = 0.0584);
MVP		0.80
ClinPred		0.12	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155041331;