12-15681305-G-GTAA

Position:

• chr12-15681305-G-GTAA

Variant summary

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

The NM_004447.6(EPS8):​c.60-4_60-3insTTA 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 0.0242 in 1,080,868 control chromosomes in the GnomAD database, including 716 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (599 hom., cov: 27)
  • Exomes 𝑓: 0.017 (117 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: 0.197

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-G-GTAA is Benign according to our data. Variant chr12-15681305-G-GTAA is described in ClinVar as [Benign]. Clinvar id is 508729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.60-4_60-3insTTA		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.60-4_60-3insTTA		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10467 AN: 146870 Hom.: 600 Cov.: 27

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.0359

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0769

GnomAD3 exomes AF: 0.0142 AC: 2173 AN: 152932 Hom.: 6 AF XY: 0.0144 AC XY: 1230 AN XY: 85482

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.00357

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0168 AC: 15680 AN: 933970 Hom.: 117 Cov.: 11 AF XY: 0.0173 AC XY: 8158 AN XY: 470376

Gnomad4 AFR exome AF: 0.0769

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.0210

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.0258

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0245

GnomAD4 genome AF: 0.0713 AC: 10470 AN: 146898 Hom.: 599 Cov.: 27 AF XY: 0.0702 AC XY: 5016 AN XY: 71450

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.0502

Gnomad4 ASJ AF: 0.0590

Gnomad4 EAS AF: 0.0365

Gnomad4 SAS AF: 0.0528

Gnomad4 FIN AF: 0.0316

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0770

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	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;