chr12-15681305-GTAATAA-G

Position:

• chr12-15681305-GTAATAA-G

Variant summary

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

The ENST00000281172.10(EPS8):​c.60-9_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 0.002 in 1,082,266 control chromosomes in the GnomAD database, including 26 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (23 hom., cov: 27)
  • Exomes 𝑓: 0.00092 (3 hom.)
• Consequence: EPS8 ENST00000281172.10 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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-GTAATAA-G is Benign according to our data. Variant chr12-15681305-GTAATAA-G is described in ClinVar as [Benign]. Clinvar id is 585852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-15681305-GTAATAA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00887 (1304/146980) while in subpopulation AFR AF= 0.0306 (1223/39954). AF 95% confidence interval is 0.0292. There are 23 homozygotes in gnomad4. There are 613 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPS8	NM_004447.6	c.60-9_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.60-9_60-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	ENSP00000281172	P1

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1297 AN: 146952 Hom.: 23 Cov.: 27

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.000982

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.000438

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000389

Gnomad OTH AF: 0.00300

GnomAD3 exomes AF: 0.000850 AC: 130 AN: 152932 Hom.: 2 AF XY: 0.000620 AC XY: 53 AN XY: 85482

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000339

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.000238

Gnomad SAS exome AF: 0.000287

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000644

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000920 AC: 860 AN: 935286 Hom.: 3 AF XY: 0.000877 AC XY: 413 AN XY: 471044

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.000948

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.000632

Gnomad4 SAS exome AF: 0.000329

Gnomad4 FIN exome AF: 0.000309

Gnomad4 NFE exome AF: 0.000388

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00887 AC: 1304 AN: 146980 Hom.: 23 Cov.: 27 AF XY: 0.00857 AC XY: 613 AN XY: 71498

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.00224

Gnomad4 ASJ AF: 0.00146

Gnomad4 EAS AF: 0.000986

Gnomad4 SAS AF: 0.000431

Gnomad4 FIN AF: 0.000438

Gnomad4 NFE AF: 0.000389

Gnomad4 OTH AF: 0.00298

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2018	- -

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;