chr1-51361249-T-C

Position:

• chr1-51361249-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001981.3(EPS15):​c.2466A>G​(p.Ile822Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,613,240 control chromosomes in the GnomAD database, including 46,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7978 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38099 hom.)
• Consequence: EPS15 NM_001981.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.699

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.566112E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS15	NM_001981.3	c.2466A>G	p.Ile822Met	missense_variant	24/25	ENST00000371733.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS15	ENST00000371733.8	c.2466A>G	p.Ile822Met	missense_variant	24/25	1	NM_001981.3	P3

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43282 AN: 151974 Hom.: 7935 Cov.: 32

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.195 AC: 49089 AN: 251336 Hom.: 6458 AF XY: 0.191 AC XY: 25909 AN XY: 135840

Gnomad AFR exome AF: 0.528

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.0119

Gnomad SAS exome AF: 0.123

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.217 AC: 317049 AN: 1461148 Hom.: 38099 Cov.: 32 AF XY: 0.214 AC XY: 155617 AN XY: 726908

Gnomad4 AFR exome AF: 0.532

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.00741

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.285 AC: 43375 AN: 152092 Hom.: 7978 Cov.: 32 AF XY: 0.275 AC XY: 20486 AN XY: 74362

Gnomad4 AFR AF: 0.521

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.248

Alfa AF: 0.234 Hom.: 11965

Bravo AF: 0.303

TwinsUK AF: 0.220 AC: 815

ALSPAC AF: 0.229 AC: 883

ESP6500AA AF: 0.514 AC: 2266

ESP6500EA AF: 0.230 AC: 1982

ExAC AF: 0.206 AC: 25064

Asia WGS AF: 0.102 AC: 357 AN: 3478

EpiCase AF: 0.229

EpiControl AF: 0.229

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0094	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.013	T;T
MetaRNN	Benign	0.00016	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.81	N;N
REVEL	Benign	0.086
Sift	Benign	0.22	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0010	B;B
Vest4		0.025
MPC		0.13
ClinPred		0.0092	T
GERP RS		5.8
Varity_R		0.040
gMVP		0.036

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17567; hg19: chr1-51826921; COSMIC: COSV65541248;