chr1-109751321-C-T

Variant names:

• chr1-109751321-C-T
• rs76425431
• NM_133181.4:c.1594G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_133181.4(EPS8L3):​c.1594G>A​(p.Glu532Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,918 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: EPS8L3 NM_133181.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.99
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016572148).
• BP6: Variant 1-109751321-C-T is Benign according to our data. Variant chr1-109751321-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3045009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 157 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133181.4. 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
	EPS8L3	NM_133181.4	MANE Select	c.1594G>A	p.Glu532Lys	missense	Exon 17 of 19	NP_573444.2
	EPS8L3	NM_139053.3		c.1597G>A	p.Glu533Lys	missense	Exon 17 of 19	NP_620641.1	Q8TE67-3
	EPS8L3	NM_024526.4		c.1504G>A	p.Glu502Lys	missense	Exon 17 of 19	NP_078802.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8L3	ENST00000361965.9	TSL:1 MANE Select	c.1594G>A	p.Glu532Lys	missense	Exon 17 of 19	ENSP00000355255.4	Q8TE67-1
	EPS8L3	ENST00000369805.7	TSL:1	c.1597G>A	p.Glu533Lys	missense	Exon 17 of 19	ENSP00000358820.3	Q8TE67-3
	EPS8L3	ENST00000361852.8	TSL:1	c.1504G>A	p.Glu502Lys	missense	Exon 17 of 19	ENSP00000354551.4	Q8TE67-2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00132 AC: 332 AN: 251034 AF XY: 0.00129

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00135 AC: 1971 AN: 1461640 Hom.: 5 Cov.: 31 AF XY: 0.00134 AC XY: 975 AN XY: 727092

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00179 AC: 80 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86212

European-Finnish (FIN) AF: 0.000282 AC: 15 AN: 53280

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00148 AC: 1651 AN: 1111968

Other (OTH) AF: 0.00129 AC: 78 AN: 60396

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74468

African (AFR) AF: 0.000385 AC: 16 AN: 41552

American (AMR) AF: 0.00190 AC: 29 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00141 Hom.: 3

Bravo AF: 0.00105

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EPS8L3-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.16
Sift	Uncertain	0.014	D
Sift4G	Benign	0.17	T
Polyphen		0.65	P
Vest4		0.38
MVP		0.47
MPC		0.38
ClinPred		0.055	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.38
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs76425431; hg19: chr1-110293943;