12-15623289-TAAAAA-TAAAAAA

Variant names:

• chr12-15623289-T-TA
• rs35885542
• NM_004447.6:c.2226-3dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004447.6(EPS8):​c.2226-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0749 in 1,226,794 control chromosomes in the GnomAD database, including 1,654 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (1602 hom., cov: 31)
  • Exomes 𝑓: 0.073 (52 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00600
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 12-15623289-T-TA is Benign according to our data. Variant chr12-15623289-T-TA is described in ClinVar as Benign. ClinVar VariationId is 517652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2226-3dupT		splice_region_variant, intron_variant	Intron 19 of 20	ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.2226-3_2226-2insT		splice_region_variant, intron_variant	Intron 19 of 20	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 11932 AN: 136486 Hom.: 1597 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00528

Gnomad EAS AF: 0.00187

Gnomad SAS AF: 0.00381

Gnomad FIN AF: 0.00379

Gnomad MID AF: 0.0208

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.0653

GnomAD2 exomes AF: 0.0709 AC: 7948 AN: 112150 AF XY: 0.0623

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.0723

Gnomad ASJ exome AF: 0.0547

Gnomad EAS exome AF: 0.0622

Gnomad FIN exome AF: 0.0440

Gnomad NFE exome AF: 0.0364

Gnomad OTH exome AF: 0.0656

GnomAD4 exome AF: 0.0733 AC: 79899 AN: 1090288 Hom.: 52 Cov.: 0 AF XY: 0.0714 AC XY: 38989 AN XY: 545914

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.295 AC: 7676 AN: 26048

American (AMR) AF: 0.0646 AC: 1695 AN: 26244

Ashkenazi Jewish (ASJ) AF: 0.0658 AC: 1269 AN: 19292

East Asian (EAS) AF: 0.0523 AC: 1674 AN: 32030

South Asian (SAS) AF: 0.0723 AC: 4726 AN: 65358

European-Finnish (FIN) AF: 0.0455 AC: 1834 AN: 40344

Middle Eastern (MID) AF: 0.0637 AC: 280 AN: 4398

European-Non Finnish (NFE) AF: 0.0686 AC: 56976 AN: 830456

Other (OTH) AF: 0.0817 AC: 3769 AN: 46118

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0876 AC: 11962 AN: 136506 Hom.: 1602 Cov.: 31 AF XY: 0.0841 AC XY: 5548 AN XY: 66006

African (AFR) AF: 0.293 AC: 11189 AN: 38170

American (AMR) AF: 0.0330 AC: 444 AN: 13468

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 17 AN: 3220

East Asian (EAS) AF: 0.00188 AC: 9 AN: 4788

South Asian (SAS) AF: 0.00382 AC: 16 AN: 4188

European-Finnish (FIN) AF: 0.00379 AC: 29 AN: 7646

Middle Eastern (MID) AF: 0.0224 AC: 6 AN: 268

European-Non Finnish (NFE) AF: 0.00210 AC: 130 AN: 62016

Other (OTH) AF: 0.0649 AC: 122 AN: 1880

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 23, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Dec 21, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2226-3dupT in intron 19 of EPS8: This variant is not expected to have clinical significance because it has been identified in 29% (2115/7356) of African chrom osomes including 275 homozygotes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org/; dbSNP rs35885542). ACMG/AMP Criteria applied: BA 1 (Richards 2015).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0060
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: rs35885542; hg19: chr12-15776223; COSMIC: COSV55537774;