12-15623289-TAAAAA-TAAA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_004447.6(EPS8):c.2226-4_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 1,289,940 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (0 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000732 (10/136558) while in subpopulation NFE AF= 0.0000645 (4/62020). AF 95% confidence interval is 0.0000211. There are 0 homozygotes in gnomad4. There are 5 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.2226-4_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.2226-4_2226-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000732 AC: 10 AN: 136536 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000524

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000645

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00375 AC: 4329 AN: 1153382 Hom.: 0 AF XY: 0.00383 AC XY: 2208 AN XY: 576520

Gnomad4 AFR exome AF: 0.00294

Gnomad4 AMR exome AF: 0.00768

Gnomad4 ASJ exome AF: 0.00517

Gnomad4 EAS exome AF: 0.00338

Gnomad4 SAS exome AF: 0.00853

Gnomad4 FIN exome AF: 0.00449

Gnomad4 NFE exome AF: 0.00325

Gnomad4 OTH exome AF: 0.00370

GnomAD4 genome AF: 0.0000732 AC: 10 AN: 136558 Hom.: 0 Cov.: 31 AF XY: 0.0000757 AC XY: 5 AN XY: 66028

Gnomad4 AFR AF: 0.0000262

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000311

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000524

Gnomad4 NFE AF: 0.0000645

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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;