12-15799527-T-C

Variant names:

• chr12-15799527-T-C
• rs10846238
• ENST00000646828.1:c.-82+14035A>G

Variant summary

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

The ENST00000646828.1(EPS8):​c.-82+14035A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 152,058 control chromosomes in the GnomAD database, including 44,981 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 0.76 (44981 hom., cov: 31)
• Consequence: EPS8 ENST00000646828.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000646828.1	c.-82+14035A>G		intron_variant	Intron 3 of 23			ENSP00000494842.1
EPS8	ENST00000646918.1	c.-22+28654A>G		intron_variant	Intron 4 of 23			ENSP00000495722.1
EPS8	ENST00000647087.1	c.-22+38046A>G		intron_variant	Intron 3 of 22			ENSP00000496406.1

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115567 AN: 151940 Hom.: 44957 Cov.: 31

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.875

Gnomad FIN AF: 0.828

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.743

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

GnomAD4 genome AF: 0.761 AC: 115645 AN: 152058 Hom.: 44981 Cov.: 31 AF XY: 0.763 AC XY: 56675 AN XY: 74326

African (AFR) AF: 0.597 AC: 24743 AN: 41456

American (AMR) AF: 0.716 AC: 10947 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2652 AN: 3466

East Asian (EAS) AF: 0.893 AC: 4613 AN: 5164

South Asian (SAS) AF: 0.875 AC: 4219 AN: 4824

European-Finnish (FIN) AF: 0.828 AC: 8752 AN: 10564

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.842 AC: 57215 AN: 67982

Other (OTH) AF: 0.744 AC: 1574 AN: 2116

Alfa AF: 0.738 Hom.: 3250

Bravo AF: 0.741

Asia WGS AF: 0.870 AC: 3026 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.8
DANN	Benign	0.69
PhyloP100		-0.65

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10846238; hg19: chr12-15952461;