12-15681305-GTAATAATAATAA-G

Position:

• chr12-15681305-GTAATAATAATAA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004447.6(EPS8):​c.60-15_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 0.0000637 in 1,083,790 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000062 (6 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 12-15681305-GTAATAATAATAA-G is Benign according to our data. Variant chr12-15681305-GTAATAATAATAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 2182778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000748 (11/146964) while in subpopulation SAS AF= 0.00043 (2/4650). AF 95% confidence interval is 0.0000755. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPS8	NM_004447.6	c.60-15_60-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.60-15_60-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	ENSP00000281172	P1

Frequencies

GnomAD3 genomes AF: 0.0000748 AC: 11 AN: 146964 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000752

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.000548

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000619 AC: 58 AN: 936826 Hom.: 6 AF XY: 0.0000742 AC XY: 35 AN XY: 471848

Gnomad4 AFR exome AF: 0.0000592

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.000128

Gnomad4 NFE exome AF: 0.0000123

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000748 AC: 11 AN: 146964 Hom.: 0 Cov.: 27 AF XY: 0.000112 AC XY: 8 AN XY: 71454

Gnomad4 AFR AF: 0.0000752

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000430

Gnomad4 FIN AF: 0.000548

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

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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;