12-15681305-GTAA-G

Position:

• chr12-15681305-GTAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004447.6(EPS8):​c.60-6_60-4del 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 0.0156 in 1,058,244 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 27)
  • Exomes 𝑓: 0.018 (2 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.19

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 12-15681305-GTAA-G is Benign according to our data. Variant chr12-15681305-GTAA-G is described in ClinVar as [Benign]. Clinvar id is 769817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0025 (368/146948) while in subpopulation AFR AF= 0.00576 (230/39960). AF 95% confidence interval is 0.00515. There are 1 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.60-6_60-4del		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.60-6_60-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 366 AN: 146920 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00265

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00275

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.00209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.00150

GnomAD3 exomes AF: 0.0106 AC: 1620 AN: 152932 Hom.: 1 AF XY: 0.0114 AC XY: 975 AN XY: 85482

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00310

Gnomad SAS exome AF: 0.0213

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00958

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0177 AC: 16106 AN: 911296 Hom.: 2 AF XY: 0.0183 AC XY: 8362 AN XY: 457826

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.0325

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.00250 AC: 368 AN: 146948 Hom.: 1 Cov.: 27 AF XY: 0.00242 AC XY: 173 AN XY: 71474

Gnomad4 AFR AF: 0.00576

Gnomad4 AMR AF: 0.00271

Gnomad4 ASJ AF: 0.000292

Gnomad4 EAS AF: 0.00296

Gnomad4 SAS AF: 0.000431

Gnomad4 FIN AF: 0.00209

Gnomad4 NFE AF: 0.000868

Gnomad4 OTH AF: 0.00149

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -

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: rs201331879; hg19: chr12-15834239;