rs11102001

chr1-109757069-G-A

Variant summary

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

The NM_133181.4(EPS8L3):c.1066C>T(p.Pro356Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0785 in 1,613,934 control chromosomes in the GnomAD database, including 8,986 homozygotes. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (3233 hom., cov: 32)
  • Exomes 𝑓: 0.071 (5753 hom.)
• Consequence: EPS8L3 NM_133181.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.203

Genes affected

EPS8L3 (HGNC:21297): (EPS8 signaling adaptor L3) 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. Alternatively spliced transcript variants encoding different isoforms exist. [provided by RefSeq, Jul 2008]

(HGNC:):

GSTM5 (HGNC:4637): (glutathione S-transferase mu 5) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002686292).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8L3	NM_133181.4	c.1066C>T	p.Pro356Ser	missense_variant	12/19	ENST00000361965.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8L3	ENST00000361965.9	c.1066C>T	p.Pro356Ser	missense_variant	12/19	1	NM_133181.4	P4
	ENST00000431955.1	n.628-18003G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23009 AN: 152014 Hom.: 3230 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0547

Gnomad EAS AF: 0.00906

Gnomad SAS AF: 0.0756

Gnomad FIN AF: 0.0642

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.0936 AC: 23531 AN: 251378 Hom.: 2063 AF XY: 0.0858 AC XY: 11650 AN XY: 135854

Gnomad AFR exome AF: 0.377

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.0649

Gnomad EAS exome AF: 0.00179

Gnomad SAS exome AF: 0.0786

Gnomad FIN exome AF: 0.0605

Gnomad NFE exome AF: 0.0614

Gnomad OTH exome AF: 0.0755

GnomAD4 exome AF: 0.0709 AC: 103587 AN: 1461802 Hom.: 5753 Cov.: 32 AF XY: 0.0699 AC XY: 50842 AN XY: 727202

Gnomad4 AFR exome AF: 0.379

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.0636

Gnomad4 EAS exome AF: 0.0221

Gnomad4 SAS exome AF: 0.0805

Gnomad4 FIN exome AF: 0.0595

Gnomad4 NFE exome AF: 0.0593

Gnomad4 OTH exome AF: 0.0787

GnomAD4 genome AF: 0.151 AC: 23035 AN: 152132 Hom.: 3233 Cov.: 32 AF XY: 0.149 AC XY: 11065 AN XY: 74400

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0547

Gnomad4 EAS AF: 0.00889

Gnomad4 SAS AF: 0.0759

Gnomad4 FIN AF: 0.0642

Gnomad4 NFE AF: 0.0610

Gnomad4 OTH AF: 0.128

Alfa AF: 0.0762 Hom.: 1914

Bravo AF: 0.165

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0576 AC: 222

ESP6500AA AF: 0.365 AC: 1606

ESP6500EA AF: 0.0628 AC: 540

ExAC AF: 0.0980 AC: 11898

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.70	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Benign	0.091
Sift	Benign	0.067	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.42	B;P;B
Vest4		0.14
MPC		0.11
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11102001; hg19: chr1-110299691; COSMIC: COSV62609123; COSMIC: COSV62609123;