1-51519221-G-T

Variant names:

• chr1-51519221-G-T
• NM_001981.3:c.11C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001981.3(EPS15):​c.11C>A​(p.Ala4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000805 in 1,242,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: EPS15 NM_001981.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.132

Genes affected

EPS15 (HGNC:3419): (epidermal growth factor receptor pathway substrate 15) This gene encodes a protein that is part of the EGFR pathway. The protein is present at clatherin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2009]

OSBPL9 (HGNC:16386): (oxysterol binding protein like 9) This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain, although some members contain only the sterol-binding domain. This family member functions as a cholesterol transfer protein that regulates Golgi structure and function. Multiple transcript variants, most of which encode distinct isoforms, have been identified. Related pseudogenes have been identified on chromosomes 3, 11 and 12. [provided by RefSeq, Jul 2010]

EPS15-AS1 (HGNC:40219): (EPS15 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13886392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS15	NM_001981.3	c.11C>A	p.Ala4Glu	missense_variant	Exon 1 of 25	ENST00000371733.8	NP_001972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS15	ENST00000371733.8	c.11C>A	p.Ala4Glu	missense_variant	Exon 1 of 25	1	NM_001981.3	ENSP00000360798.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.05e-7 AC: 1 AN: 1242794 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 612842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>A (p.A4E) alteration is located in exon 1 (coding exon 1) of the EPS15 gene. This alteration results from a C to A substitution at nucleotide position 11, causing the alanine (A) at amino acid position 4 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.62	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.076
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.0010	B;B
Vest4		0.40
MutPred		0.22		Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);
MVP		0.36
MPC		0.17
ClinPred		0.61	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.44
gMVP		0.62

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: chr1-51984893;