chr1-51519221-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★). 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001981.3. 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
	EPS15	NM_001981.3	MANE Select	c.11C>A	p.Ala4Glu	missense	Exon 1 of 25	NP_001972.1	P42566-1
	EPS15	NM_001410797.1		c.11C>A	p.Ala4Glu	missense	Exon 1 of 25	NP_001397726.1	A0A994J5A3
	EPS15	NM_001410796.1		c.11C>A	p.Ala4Glu	missense	Exon 1 of 24	NP_001397725.1	A0A994J5J3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS15	ENST00000371733.8	TSL:1 MANE Select	c.11C>A	p.Ala4Glu	missense	Exon 1 of 25	ENSP00000360798.3	P42566-1
	EPS15	ENST00000371730.6	TSL:1	c.11C>A	p.Ala4Glu	missense	Exon 1 of 23	ENSP00000360795.2	B1AUU8
	EPS15	ENST00000706292.1		c.11C>A	p.Ala4Glu	missense	Exon 1 of 25	ENSP00000516336.1	A0A994J5A3

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

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

African (AFR) AF: 0.00 AC: 0 AN: 25932

American (AMR) AF: 0.00 AC: 0 AN: 23784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19704

East Asian (EAS) AF: 0.00 AC: 0 AN: 29150

South Asian (SAS) AF: 0.00 AC: 0 AN: 54968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4498

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 992790

Other (OTH) AF: 0.00 AC: 0 AN: 48452

⚠️ 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.: 31

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	0.50
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.13
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.076
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0010	B
Vest4		0.40
MutPred		0.22		Gain of loop (P = 0.1081)
MVP		0.36
MPC		0.17
ClinPred		0.61	D
GERP RS		2.1
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.44
gMVP		0.62
Mutation Taster		=79/21	polymorphism

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

hg19: chr1-51984893;