2-221443506-T-C

Variant names:

• chr2-221443506-T-C
• rs10498111
• NM_004438.5:c.1875A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004438.5(EPHA4):​c.1875A>G​(p.Lys625Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,282 control chromosomes in the GnomAD database, including 1,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (463 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1167 hom.)
• Consequence: EPHA4 NM_004438.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.20
• Publications: 9 publications found

Genes affected

EPHA4 (HGNC:3388): (EPH receptor A4) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

EPHA4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Illumina

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-221443506-T-C is Benign according to our data. Variant chr2-221443506-T-C is described in ClinVar as Benign. ClinVar VariationId is 1170394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA4	NM_004438.5	c.1875A>G	p.Lys625Lys	synonymous_variant	Exon 10 of 18	ENST00000281821.7	NP_004429.1
EPHA4	NM_001304536.2	c.1875A>G	p.Lys625Lys	synonymous_variant	Exon 11 of 19		NP_001291465.1
EPHA4	NM_001363748.2	c.1875A>G	p.Lys625Lys	synonymous_variant	Exon 10 of 18		NP_001350677.1
EPHA4	NM_001304537.2	c.1722A>G	p.Lys574Lys	synonymous_variant	Exon 9 of 17		NP_001291466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA4	ENST00000281821.7	c.1875A>G	p.Lys625Lys	synonymous_variant	Exon 10 of 18	1	NM_004438.5	ENSP00000281821.2
EPHA4	ENST00000409854.5	c.1875A>G	p.Lys625Lys	synonymous_variant	Exon 10 of 17	1		ENSP00000386276.1
EPHA4	ENST00000409938.5	c.1875A>G	p.Lys625Lys	synonymous_variant	Exon 11 of 18	2		ENSP00000386829.1

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8375 AN: 151934 Hom.: 461 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0453 AC: 11392 AN: 251300 AF XY: 0.0420

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0935

Gnomad FIN exome AF: 0.00541

Gnomad NFE exome AF: 0.00589

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0193 AC: 28188 AN: 1461230 Hom.: 1167 Cov.: 30 AF XY: 0.0203 AC XY: 14748 AN XY: 726940

African (AFR) AF: 0.134 AC: 4482 AN: 33462

American (AMR) AF: 0.106 AC: 4728 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 764 AN: 26124

East Asian (EAS) AF: 0.108 AC: 4303 AN: 39680

South Asian (SAS) AF: 0.0737 AC: 6351 AN: 86204

European-Finnish (FIN) AF: 0.00515 AC: 275 AN: 53398

Middle Eastern (MID) AF: 0.0156 AC: 90 AN: 5766

European-Non Finnish (NFE) AF: 0.00509 AC: 5654 AN: 1111534

Other (OTH) AF: 0.0255 AC: 1541 AN: 60360

GnomAD4 genome AF: 0.0553 AC: 8401 AN: 152052 Hom.: 463 Cov.: 32 AF XY: 0.0561 AC XY: 4169 AN XY: 74336

African (AFR) AF: 0.138 AC: 5709 AN: 41412

American (AMR) AF: 0.0765 AC: 1167 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3468

East Asian (EAS) AF: 0.0937 AC: 484 AN: 5166

South Asian (SAS) AF: 0.0753 AC: 362 AN: 4810

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10612

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.00584 AC: 397 AN: 68002

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0266 Hom.: 526

Bravo AF: 0.0658

Asia WGS AF: 0.0910 AC: 316 AN: 3476

EpiCase AF: 0.00796

EpiControl AF: 0.00723

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.4
DANN	Benign	0.63
PhyloP100		2.2
Mutation Taster		=99/1	polymorphism (auto)

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: rs10498111; hg19: chr2-222308226; COSMIC: COSV56034701;