rs764545146

Variant names:

• chr1-155063931-C-A
• rs764545146
• NM_005227.3:c.108C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-155063931-C-A
• chr1-155063931-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001407761.1(EFNA4-EFNA3):​c.108C>A​(p.Asn36Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: EFNA4-EFNA3 NM_001407761.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86
• Publications: 0 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:):

DCST1-AS1 (HGNC:41147): (DCST1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407761.1. 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.108C>A	p.Asn36Lys	missense	Exon 1 of 4	NP_005218.1
	EFNA4-EFNA3	NM_001407761.1		c.108C>A	p.Asn36Lys	missense	Exon 1 of 5	NP_001394690.1
	EFNA4	NM_182689.2		c.108C>A	p.Asn36Lys	missense	Exon 1 of 4	NP_872631.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNA4	ENST00000368409.8	TSL:1 MANE Select	c.108C>A	p.Asn36Lys	missense	Exon 1 of 4	ENSP00000357394.3
	EFNA4-EFNA3	ENST00000505139.1	TSL:2	c.108C>A	p.Asn36Lys	missense	Exon 1 of 5	ENSP00000426741.1
	EFNA4	ENST00000359751.8	TSL:1	c.108C>A	p.Asn36Lys	missense	Exon 1 of 4	ENSP00000352789.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403430 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 694974

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000332 AC: 1 AN: 30130

American (AMR) AF: 0.00 AC: 0 AN: 37394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25038

East Asian (EAS) AF: 0.00 AC: 0 AN: 34484

South Asian (SAS) AF: 0.00 AC: 0 AN: 79116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084672

Other (OTH) AF: 0.00 AC: 0 AN: 58040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.9
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.74		Gain of methylation at N36 (P = 0.0157)
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		0.040	Neutral
Varity_R		0.89
gMVP		0.76
Mutation Taster		=27/73	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: rs764545146; hg19: chr1-155036407;