1-155066794-C-T

Position:

• chr1-155066794-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_005227.3(EFNA4):​c.178C>T​(p.His60Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00216 in 1,612,736 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: EFNA4 NM_005227.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.68

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3530325).
• BP6: Variant 1-155066794-C-T is Benign according to our data. Variant chr1-155066794-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1554935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155066794-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 205 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFNA4	NM_005227.3	c.178C>T	p.His60Tyr	missense_variant	2/4	ENST00000368409.8	NP_005218.1
EFNA4-EFNA3	NM_001407761.1	c.113+2858C>T		intron_variant			NP_001394690.1
ADAM15-EFNA4	NR_176418.1	n.3615C>T		non_coding_transcript_exon_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFNA4	ENST00000368409.8	c.178C>T	p.His60Tyr	missense_variant	2/4	1	NM_005227.3	ENSP00000357394
EFNA4	ENST00000359751.8	c.178C>T	p.His60Tyr	missense_variant	2/4	1		ENSP00000352789	P2
EFNA4	ENST00000427683.2	c.178C>T	p.His60Tyr	missense_variant	2/4	2		ENSP00000414378	A2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152248 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00217

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00131 AC: 327 AN: 249144 Hom.: 2 AF XY: 0.00149 AC XY: 201 AN XY: 134972

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000731

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00181

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00225 AC: 3285 AN: 1460370 Hom.: 10 Cov.: 32 AF XY: 0.00220 AC XY: 1599 AN XY: 726590

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000744

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.00265

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152366 Hom.: 1 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74518

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00193 Hom.: 1

Bravo AF: 0.00145

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00302

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.039	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.84
MVP		0.97
MPC		1.5
ClinPred		0.098	T
GERP RS		5.3
Varity_R		0.62
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs148289726; hg19: chr1-155039270;