12-15623289-TAAAAA-TAAAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_004447.6(EPS8):c.2226-3del 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 0.00336 in 136,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.26 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPS8 NM_004447.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -12 ACMG points.

• BP6: Variant 12-15623289-TA-T is Benign according to our data. Variant chr12-15623289-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 666690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00336 (458/136300) while in subpopulation NFE AF= 0.0034 (210/61822). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.2226-3del		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.2226-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 458 AN: 136278 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00290

Gnomad ASJ AF: 0.00342

Gnomad EAS AF: 0.00187

Gnomad SAS AF: 0.000952

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00347

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00430

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.258 AC: 238488 AN: 925642 Hom.: 0 Cov.: 0 AF XY: 0.263 AC XY: 121339 AN XY: 461256

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.255

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.00336 AC: 458 AN: 136300 Hom.: 0 Cov.: 31 AF XY: 0.00408 AC XY: 269 AN XY: 65870

Gnomad4 AFR AF: 0.00165

Gnomad4 AMR AF: 0.00283

Gnomad4 ASJ AF: 0.00342

Gnomad4 EAS AF: 0.00188

Gnomad4 SAS AF: 0.000955

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00481

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2018

c.2226-3delT in intron 19 of EPS8: This variant is likely benign because it is n ot predicted to impact splicing. Furthermore, this variant is a deletion of 1 of 13 consecutive Ts in the intron, which is a repetivie region without known fu nction. ACMG/AMP Criteria applied: BP3, BP4. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;