rs12609976

Positions:

• chr19-55076454-G-A

Variant summary

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

The ENST00000201647.11(EPS8L1):​c.10G>A​(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,611,606 control chromosomes in the GnomAD database, including 18,825 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 0.13 (1508 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17317 hom.)
• Consequence: EPS8L1 ENST00000201647.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240

Genes affected

EPS8L1 (HGNC:21295): (EPS8 signaling adaptor L1) This gene encodes a protein that is related to epidermal growth factor receptor pathway substrate 8 (EPS8), a substrate for the epidermal growth factor receptor. The function of this protein is unknown. At least two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015839636).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPS8L1	NM_133180.3	c.10G>A	p.Ala4Thr	missense_variant	2/20	ENST00000201647.11	NP_573441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPS8L1	ENST00000201647.11	c.10G>A	p.Ala4Thr	missense_variant	2/20	1	NM_133180.3	ENSP00000201647	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19575 AN: 152040 Hom.: 1506 Cov.: 32

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.0936

Gnomad SAS AF: 0.0957

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.139 AC: 34377 AN: 247254 Hom.: 2642 AF XY: 0.142 AC XY: 19090 AN XY: 134264

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.0920

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.151 AC: 219905 AN: 1459448 Hom.: 17317 Cov.: 33 AF XY: 0.151 AC XY: 109294 AN XY: 725980

Gnomad4 AFR exome AF: 0.0490

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.129 AC: 19583 AN: 152158 Hom.: 1508 Cov.: 32 AF XY: 0.126 AC XY: 9408 AN XY: 74386

Gnomad4 AFR AF: 0.0542

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.0931

Gnomad4 SAS AF: 0.0956

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.130

Alfa AF: 0.160 Hom.: 3615

Bravo AF: 0.124

TwinsUK AF: 0.158 AC: 585

ALSPAC AF: 0.157 AC: 606

ESP6500AA AF: 0.0538 AC: 237

ESP6500EA AF: 0.167 AC: 1436

ExAC AF: 0.137 AC: 16656

Asia WGS AF: 0.111 AC: 388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.33
DANN	Benign	0.19
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00014	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.27
ClinPred		0.00011	T
GERP RS		2.5
Varity_R		0.037
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12609976; hg19: chr19-55587822; COSMIC: COSV52380751; COSMIC: COSV52380751;