rs751948150

Positions:

• chr12-15681305-G-GTAATAATAA
• chr12-15681305-GTAATAATAATAA-G
• chr12-15681305-G-GTAATAATAATAATAATAA
• chr12-15681305-G-GTAATAATAATAATAA
• chr12-15681305-GTAATAATAA-G
• chr12-15681305-G-GTAATAATAATAA
• chr12-15681305-G-GTAA
• chr12-15681305-GTAATAA-G
• chr12-15681305-G-GTAATAA
• chr12-15681305-GTAATAATAATAATAA-G
• chr12-15681305-GTAA-G
• chr12-15681305-G-GTAATAATAATAATAATAATAA

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.60-4_60-3insTTATTATTA 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 0.00147 in 1,083,770 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 27)
  • Exomes 𝑓: 0.00086 (1 hom.)
• 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: 0.197

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-GTAATAATAA is Benign according to our data. Variant chr12-15681305-G-GTAATAATAA is described in ClinVar as [Likely_benign]. Clinvar id is 724500.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 = 0.00533 (784/146968) while in subpopulation AFR AF= 0.0129 (517/39952). AF 95% confidence interval is 0.012. There are 4 homozygotes in gnomad4. There are 410 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 781 AN: 146940 Hom.: 3 Cov.: 27

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.00530

Gnomad SAS AF: 0.000860

Gnomad FIN AF: 0.00976

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00350

GnomAD3 exomes AF: 0.000942 AC: 144 AN: 152932 Hom.: 0 AF XY: 0.000877 AC XY: 75 AN XY: 85482

Gnomad AFR exome AF: 0.000793

Gnomad AMR exome AF: 0.000135

Gnomad ASJ exome AF: 0.000845

Gnomad EAS exome AF: 0.000238

Gnomad SAS exome AF: 0.000402

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000860 AC: 806 AN: 936802 Hom.: 1 Cov.: 11 AF XY: 0.000854 AC XY: 403 AN XY: 471830

Gnomad4 AFR exome AF: 0.00408

Gnomad4 AMR exome AF: 0.000535

Gnomad4 ASJ exome AF: 0.000354

Gnomad4 EAS exome AF: 0.00112

Gnomad4 SAS exome AF: 0.000246

Gnomad4 FIN exome AF: 0.00378

Gnomad4 NFE exome AF: 0.000641

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00533 AC: 784 AN: 146968 Hom.: 4 Cov.: 27 AF XY: 0.00574 AC XY: 410 AN XY: 71490

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00117

Gnomad4 EAS AF: 0.00532

Gnomad4 SAS AF: 0.000862

Gnomad4 FIN AF: 0.00976

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.00348

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EPS8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2023

- -

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;