12-15623289-T-TA

Position:

• chr12-15623289-T-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004447.6(EPS8):​c.2226-3_2226-2insT variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00600

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
EPS8	NM_004447.6	c.2226-3_2226-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10	c.2226-3_2226-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	P1

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

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

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.0646

Gnomad4 ASJ exome AF: 0.0658

Gnomad4 EAS exome AF: 0.0523

Gnomad4 SAS exome AF: 0.0723

Gnomad4 FIN exome AF: 0.0455

Gnomad4 NFE exome AF: 0.0686

Gnomad4 OTH exome AF: 0.0817

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

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.0330

Gnomad4 ASJ AF: 0.00528

Gnomad4 EAS AF: 0.00188

Gnomad4 SAS AF: 0.00382

Gnomad4 FIN AF: 0.00379

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.0649

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2017

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs35885542; hg19: chr12-15776223;