rs10505786

Variant names:

• chr12-15708037-G-C
• rs10505786
• NM_004447.6:c.-21-25065C>G

Variant summary

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

The NM_004447.6(EPS8):​c.-21-25065C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,138 control chromosomes in the GnomAD database, including 2,868 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 0.17 (2868 hom., cov: 32)
• Consequence: EPS8 NM_004447.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 2 publications found

Genes affected

EPS8 (HGNC:3420): (EGFR pathway substrate 8, signaling adaptor) This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

EPS8 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 102

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.-21-25065C>G		intron_variant	Intron 1 of 20	ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.-21-25065C>G		intron_variant	Intron 1 of 20	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26454 AN: 152020 Hom.: 2862 Cov.: 32

Gnomad AFR AF: 0.0849

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.207

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.174 AC: 26465 AN: 152138 Hom.: 2868 Cov.: 32 AF XY: 0.177 AC XY: 13141 AN XY: 74360

African (AFR) AF: 0.0847 AC: 3517 AN: 41530

American (AMR) AF: 0.340 AC: 5197 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 840 AN: 3472

East Asian (EAS) AF: 0.103 AC: 531 AN: 5174

South Asian (SAS) AF: 0.130 AC: 627 AN: 4822

European-Finnish (FIN) AF: 0.210 AC: 2218 AN: 10578

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12909 AN: 67972

Other (OTH) AF: 0.205 AC: 432 AN: 2110

Alfa AF: 0.184 Hom.: 366

Bravo AF: 0.184

Asia WGS AF: 0.119 AC: 414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.53
DANN	Benign	0.40
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10505786; hg19: chr12-15860971;