rs2274536

Variant names:

• chr1-109751955-A-G
• rs2274536
• NM_133181.4:c.1434+40T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133181.4(EPS8L3):​c.1434+40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,565,574 control chromosomes in the GnomAD database, including 79,918 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.

• Frequency:
  • Genomes: 𝑓 0.38 (12615 hom., cov: 31)
  • Exomes 𝑓: 0.30 (67303 hom.)
• Consequence: EPS8L3 NM_133181.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.368
• Publications: 22 publications found

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]

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]

ENSG00000241720 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8L3	NM_133181.4	c.1434+40T>C		intron_variant	Intron 15 of 18	ENST00000361965.9	NP_573444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8L3	ENST00000361965.9	c.1434+40T>C		intron_variant	Intron 15 of 18	1	NM_133181.4	ENSP00000355255.4

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57399 AN: 151740 Hom.: 12586 Cov.: 31

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.296 AC: 63577 AN: 214480 AF XY: 0.291

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.301 AC: 425811 AN: 1413716 Hom.: 67303 Cov.: 32 AF XY: 0.300 AC XY: 209501 AN XY: 697630

African (AFR) AF: 0.617 AC: 19863 AN: 32174

American (AMR) AF: 0.231 AC: 9267 AN: 40152

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 7573 AN: 22658

East Asian (EAS) AF: 0.116 AC: 4549 AN: 39320

South Asian (SAS) AF: 0.295 AC: 22860 AN: 77596

European-Finnish (FIN) AF: 0.273 AC: 14030 AN: 51398

Middle Eastern (MID) AF: 0.320 AC: 1764 AN: 5504

European-Non Finnish (NFE) AF: 0.302 AC: 327926 AN: 1086666

Other (OTH) AF: 0.309 AC: 17979 AN: 58248

GnomAD4 genome AF: 0.378 AC: 57478 AN: 151858 Hom.: 12615 Cov.: 31 AF XY: 0.372 AC XY: 27636 AN XY: 74232

African (AFR) AF: 0.608 AC: 25180 AN: 41382

American (AMR) AF: 0.287 AC: 4378 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1147 AN: 3470

East Asian (EAS) AF: 0.109 AC: 564 AN: 5168

South Asian (SAS) AF: 0.291 AC: 1400 AN: 4804

European-Finnish (FIN) AF: 0.285 AC: 3006 AN: 10550

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20565 AN: 67902

Other (OTH) AF: 0.332 AC: 699 AN: 2108

Alfa AF: 0.327 Hom.: 27119

Bravo AF: 0.386

Asia WGS AF: 0.227 AC: 791 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.68
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2274536; hg19: chr1-110294577; COSMIC: COSV62610112; COSMIC: COSV62610112;