1-155085133-C-G

Position:

• chr1-155085133-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000368408.4(EFNA3):​c.171C>G​(p.Asp57Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EFNA3 ENST00000368408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.160

Genes affected

EFNA3 (HGNC:3223): (ephrin A3) 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. [provided by RefSeq, Jul 2008]

EFNA4-EFNA3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFNA3	NM_004952.5	c.171C>G	p.Asp57Glu	missense_variant	2/5	ENST00000368408.4	NP_004943.1
EFNA4-EFNA3	NM_001407761.1	c.156C>G	p.Asp52Glu	missense_variant	2/5		NP_001394690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFNA3	ENST00000368408.4	c.171C>G	p.Asp57Glu	missense_variant	2/5	1	NM_004952.5	ENSP00000357393	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2023

The c.171C>G (p.D57E) alteration is located in exon 2 (coding exon 2) of the EFNA3 gene. This alteration results from a C to G substitution at nucleotide position 171, causing the aspartic acid (D) at amino acid position 57 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;D
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.81		.;Loss of stability (P = 0.2329);
MVP		0.54
MPC		2.2
ClinPred		1.0	D
GERP RS		-4.8
Varity_R		0.83
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155057609;