chr1-51400939-C-T

Variant names:

• chr1-51400939-C-T
• rs761020364
• NM_001981.3:c.1897G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001981.3(EPS15):​c.1897G>A​(p.Asp633Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000693 in 1,586,306 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: EPS15 NM_001981.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74
• Publications: 2 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21511826).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

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.1897G>A	p.Asp633Asn	missense	Exon 19 of 25	NP_001972.1	P42566-1
	EPS15	NM_001410797.1		c.2008G>A	p.Asp670Asn	missense	Exon 19 of 25	NP_001397726.1	A0A994J5A3
	EPS15	NM_001410796.1		c.1807G>A	p.Asp603Asn	missense	Exon 18 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.1897G>A	p.Asp633Asn	missense	Exon 19 of 25	ENSP00000360798.3	P42566-1
	EPS15	ENST00000371730.6	TSL:1	c.1495G>A	p.Asp499Asn	missense	Exon 17 of 23	ENSP00000360795.2	B1AUU8
	EPS15	ENST00000706292.1		c.2008G>A	p.Asp670Asn	missense	Exon 19 of 25	ENSP00000516336.1	A0A994J5A3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 232848 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000558 AC: 8 AN: 1434252 Hom.: 0 Cov.: 26 AF XY: 0.00000700 AC XY: 5 AN XY: 713912

African (AFR) AF: 0.00 AC: 0 AN: 32048

American (AMR) AF: 0.00 AC: 0 AN: 40676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25736

East Asian (EAS) AF: 0.00 AC: 0 AN: 38228

South Asian (SAS) AF: 0.0000487 AC: 4 AN: 82170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1097156

Other (OTH) AF: 0.00 AC: 0 AN: 59300

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74272

African (AFR) AF: 0.0000483 AC: 2 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

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	Benign	0.27
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0096	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.13
Sift	Benign	0.80	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.38
MutPred		0.13		Gain of catalytic residue at D633 (P = 0.0801)
MVP		0.51
MPC		0.43
ClinPred		0.84	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.21
gMVP		0.19
Mutation Taster		=88/12	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

dbSNP: rs761020364; hg19: chr1-51866611;