rs778254637

Variant names:

• chr17-7705638-G-A
• rs778254637
• NM_001406.4:c.40G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7705638-G-A
• chr17-7705638-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001406.4(EFNB3):​c.40G>A​(p.Gly14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,364,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: EFNB3 NM_001406.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26
• Publications: 0 publications found

Genes affected

EFNB3 (HGNC:3228): (ephrin B3) EFNB3, a member of the ephrin gene family, is important in brain development as well as in its maintenance. Moreover, since levels of EFNB3 expression were particularly high in several forebrain subregions compared to other brain subregions, it may play a pivotal role in forebrain function. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, particularly in the nervous system. EPH Receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin ligands and receptors have been named by the Eph Nomenclature Committee (1997). 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. The Eph family of receptors are similarly divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34313744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406.4. 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
	EFNB3	NM_001406.4	MANE Select	c.40G>A	p.Gly14Arg	missense	Exon 1 of 5	NP_001397.1	Q15768

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNB3	ENST00000226091.3	TSL:1 MANE Select	c.40G>A	p.Gly14Arg	missense	Exon 1 of 5	ENSP00000226091.2	Q15768

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000185 AC: 3 AN: 162014 AF XY: 0.0000109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1364318 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 677576

African (AFR) AF: 0.00 AC: 0 AN: 27174

American (AMR) AF: 0.00 AC: 0 AN: 25888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23168

East Asian (EAS) AF: 0.00 AC: 0 AN: 32800

South Asian (SAS) AF: 0.0000413 AC: 3 AN: 72630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079476

Other (OTH) AF: 0.00 AC: 0 AN: 56710

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.50
Sift	Benign	0.13	T
Sift4G	Benign	0.34	T
Polyphen		0.020	B
Vest4		0.47
MutPred		0.71		Gain of methylation at G14 (P = 0.0115)
MVP		0.93
MPC		1.4
ClinPred		0.41	T
GERP RS		4.0
PromoterAI		-0.017	Neutral
Varity_R		0.17
gMVP		0.87

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: rs778254637; hg19: chr17-7608956;